Novel indoline compound and medicinal use thereof

ABSTRACT

The present invention provides an indoline compound represented by the formula (I)  
                 
wherein each symbol is as defined in the DESCRIPTION, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing this indoline compound or a pharmaceutically acceptable salt thereof. The compound of the present invention shows superior ACAT inhibitory effect and superior lipoperoxidation inhibitory effect and is useful as an ACAT inhibitor or a lipoperoxidation inhibitor.

TECHNICAL FIELD

The present invention relates to a novel indoline compound andpharmaceutical use thereof. More particularly, the present inventionrelates to a novel indoline compound having an inhibitory activity onacyl-CoA: cholesterol acyltransferase (hereinafter ACAT) andlipoperoxidation inhibitory activity, or to pharmaceutical use thereof.

BACKGROUND ART

It is a well-known fact that arteriosclerosis is an extremely importantfactor causing various circulatory diseases, and active studies havebeen undertaken in an attempt to achieve suppression of the evolution ofarteriosclerosis or regression thereof.

In recent years, it has been clarified that cholesterol in blood isaccumulated in arterial walls as a cholesterol ester, and that itsignificantly evolves arteriosclerosis. Therefore, a decrease incholesterol level in blood leads to the reduction of accumulation ofcholesterol ester in arterial walls, and is effective for thesuppression of evolution of arteriosclerosis and regression thereof. Asa pharmaceutical agent that decreases cholesterol in blood, acholesterol synthesis inhibitor, a bile acid absorption inhibitor andthe like are used and their effectiveness has been acknowledged.However, an ideal pharmaceutical agent that shows clear clinical effectand less side effects has not been realized yet.

Cholesterol in food is esterified in mucous membrane of small intestine,and taken into blood as chylomicron. ACAT is known to play an importantrole in the generation of cholesterol ester in mucous membrane of smallintestine. In addition, cholesterol synthesized in the liver isesterified by ACAT and secreted into blood as a very low densitylipoprotein (VLDL). Accordingly, suppression of esterification ofcholesterol by inhibition of ACAT in the mucosal membrane of the smallintestine and liver is considered to decrease cholesterol level ofblood.

A pharmaceutical agent which more directly inhibits deposition ofcholesterol in arterial walls has been desired as a pharmaceutical agentwhich more effectively prevents or treats arteriosclerosis, and studiesin this field are thriving. Yet, an ideal pharmaceutical agent has notbeen developed. In arterial walls, ACAT in macrophages or smooth musclecells esterifies cholesterol and causes accumulation of cholesterolester. Therefore, inhibition of ACAT in arterial walls is expected toeffectively suppress accumulation of cholesterol ester.

From the foregoing, it is concluded that an ACAT inhibitor will make aneffective pharmaceutical agent for hyperlipemia and arteriosclerosis, asa result of suppression of absorption of cholesterol in small intestine,secretion of cholesterol from liver and accumulation of cholesterol inarterial walls.

Conventionally, there have been reported, for example, as such ACATinhibitors, amide and urea derivatives [J. Med. Chem., 29: 1131 (1986),Japanese Patent Unexamined Publication Nos. 117651/1990, 7259/1990,234839/1992, 327564/1992 and 32666/1993]. However, creation andpharmacological studies of these compounds have been far fromsufficient. First of all, in these compounds, it is not clear if theblood cholesterol lowering action and cholesterol accumulationsuppressing effect in arterial wall due to an ACAT inhibitory effect isclinically sufficiently effective for the suppression of evolution ofarteriosclerosis and regression thereof. Since most of the conventionalACAT inhibitors are extremely highly fat-soluble, oral absorption isoften low, and when oral absorption is fine, organopathy in adrenal,liver and the like is feared to be induced. Furthermore, a highlyfat-soluble, low absorptive ACAT inhibitor ay clinically cause diarrhea.

Meanwhile, hyperoxidation of low density lipoprotein (LDL) is alsohighly responsible for intracellular incorporation of cholesterolaccumulated as cholesterol ester in arterial walls.

In addition, it is known that hyperoxidation of lipids in a livingorganism is deeply concerned with the onset of arteriosclerosis andcerebrovascular and cardiovascular ischemic diseases.

Accordingly, a compound having both an ACAT inhibitory activity andlipoperoxidation inhibitory activity is highly useful as apharmaceutical product, since it effectively and certainly reducesaccumulation of cholesterol ester in arterial walls and inhibitslipoperoxidation in living organisms, thereby preventing and treatingvarious vascular diseases caused thereby.

It is therefore an object of the present invention to provide a compoundhaving ACAT inhibitory activity and lipoperoxidation inhibitoryactivity, as well as pharmaceutical use thereof, particularly ACATinhibitor and lipoperoxidation inhibitor.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies in an attempt toachieve the aforementioned objects and found that the novel indolinecompound of the present invention not only has a strong ACAT inhibitoryeffect but also a lipoperoxidation inhibitory effect, superior oralabsorbability, and a strong anti-hyperlipidemia effect and ananti-arteriosclerosis effect, which resulted in the completion of thepresent invention.

Accordingly, the present invention provides

-   1) a novel indoline compound represented by the formula (I)    wherein-   R¹ and R³ are the same or different and each is hydrogen atom, lower    alkyl group or lower alkoxy group,-   R² is —NO₂, —NHSO₂R⁶ [R⁶ is alkyl group, aryl group or —NHR⁷ (R⁷ is    hydrogen atom, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group) or    lower alkoxycarbonyl group)], —NHCONH₂ or lower alkyl group    substituted by —NHSO₂R⁶ [R⁶ is alkyl group, aryl group or —NHR⁷ (R⁷    is hydrogen atom, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group)    or lower alkoxycarbonyl group)],-   R⁴ is hydrogen atom, alkyl group optionally substituted by hydroxy    group, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group), lower    alkenyl group, lower alkoxy lower alkyl group, lower alkylthio lower    alkyl group, cycloalkyl group or cycloalkylalkyl group,-   R⁵ is alkyl group, cycloalkyl group or aryl group,-   R¹² is hydrogen atom, lower alkyl group, lower alkoxy lower alkyl    group or lower alkylthio lower alkyl group,    or a pharmaceutically acceptable salt thereof,-   2) the novel indoline compound of the above-mentioned 1), wherein,    in the formula (I), R¹ and R³ are the same or different and each is    hydrogen atom, lower alkyl group or lower alkoxy group, R² is —NO₂,    —NHSO₂R⁶ [R⁶ is alkyl group, aryl group or —NHR⁷ (R⁷ is hydrogen    atom, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group) or lower    alkoxycarbonyl group)], —NHCONH₂ or lower alkyl group substituted by    —NHSO₂R⁶ [R⁶ is alkyl group, aryl group or —NHR⁷ (R⁷ is hydrogen    atom, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group) or lower    alkoxycarbonyl group)], R⁴ is hydrogen atom, alkyl group, cycloalkyl    group or cycloalkylalkyl group, R⁵ is alkyl group, cycloalkyl group    or aryl group, and R¹² is hydrogen atom, or a pharmaceutically    acceptable salt thereof,-   3) the novel indoline compound of the above-mentioned 1), wherein,    in the formula (I), R² is —NHSO₂R⁶ [R⁶ is alkyl group or —NHR⁷ (R⁷    is hydrogen atom)], R⁴ is alkyl group optionally substituted by    hydroxy group, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group),    lower alkenyl group, lower alkoxy lower alkyl group or lower    alkylthio lower alkyl group, R⁵ is alkyl group, R¹² is hydrogen    atom, lower alkyl group, lower alkoxy lower alkyl group or lower    alkylthio lower alkyl group, or a pharmaceutically acceptable salt    thereof,-   4) the novel indoline compound of the above-mentioned 2), wherein,    in the formula (I), R² is —NHSO₂R⁶ [R⁶ is alkyl group or —NHR⁷ (R⁷    is hydrogen atom)] or —NHCONH₂, or a pharmaceutically acceptable    salt thereof,-   5) the novel indoline compound of the above-mentioned 2), wherein,    in the formula (I), R² or —NHCOR⁵ is bonded to the 5-position of    indoline, and the other is bonded to the 7-position of indoline, or    a pharmaceutically acceptable salt thereof,-   6) the novel indoline compound of the above-mentioned 3), wherein,    in the formula (I), R² is bonded to the 5-position of indoline, and    —NHCOR⁵ is bonded to the 7-position of indoline, or a    pharmaceutically acceptable salt thereof,-   7) the novel indoline compound of the above-mentioned 4), wherein,    in the formula (I), R² is bonded to the 5-position of indoline, and    —NHCOR⁵ is bonded to the 7-position of indoline, or a    pharmaceutically acceptable salt thereof,-   8) the novel indoline compound of the above-mentioned 6), wherein,    in the formula (I), R⁴ is lower alkoxy lower alkyl group or lower    alkylthio lower alkyl group, and R is hydrogen atom or lower alkyl    group, or a pharmaceutically acceptable salt thereof,-   9) the novel indoline compound of the above-mentioned 8), wherein,    in the formula (I), R¹ and R³ are lower alkyl groups, or a    pharmaceutically acceptable salt thereof,-   10) the novel indoline compound of the above-mentioned 6), wherein,    in the formula (I), R¹² is bonded to the 2-position of indoline, or    a pharmaceutically acceptable salt thereof,-   11) the novel indoline compound of the above-mentioned 10), wherein,    in the formula (I), R⁴ is alkyl group, R¹² is lower alkoxy lower    alkyl group or lower alkylthio lower alkyl group, or a    pharmaceutically acceptable salt thereof,-   12) the novel indoline compound of the above-mentioned 11), wherein,    in the formula (I), R³ and R³ are lower alkyl groups, or a    pharmaceutically acceptable salt thereof,-   13) the novel indoline compound of the above-mentioned 7), wherein,    in the formula (I), R¹ and R³ are lower alkyl groups, and R⁵ is    alkyl group, or a pharmaceutically acceptable salt thereof,-   14) the novel indoline compound of the above-mentioned 13), wherein,    in the formula (I), R² is —NHSO₂R⁶ (R⁶ is alkyl group), or a    pharmaceutically acceptable salt thereof,-   15) the novel indoline compound of the above-mentioned 13), wherein,    in the formula (I), R² is —NHSO₂R⁶ [R⁶ is —NHR⁷ (R⁷ is hydrogen    atom)], or a pharmaceutically acceptable salt thereof,-   16) the novel indoline compound of the above-mentioned 13), wherein,    in the formula (I), R² is —NHCONH₂, or a pharmaceutically acceptable    salt thereof,-   17) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is any of the following (1)-(5), or    a pharmaceutically acceptable salt thereof:-   (1)    N-(5-methanesulfonylamino-4,6-dimethyl-1-propylindolin-7-yl)-2,2-dimethylpropanamide,-   (2)    N-[5-methanesulfonylamino-4,6-dimethyl-1-(2-methylpropyl)indolin-7-yl]-2,2-dimethylpropanamide,-   (3)    N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,-   (4)    N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methylbutyl)indolin-7-yl]-2,2-dimethylpropanamide,-   (5)    N-(5-methanesulfonylamino-4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide,-   18) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is the following (1) or, (2), or a    pharmaceutically acceptable salt thereof:-   (1)    N-(5-methanesulfonylamino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide,-   (2)    N-(1-hexyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,-   19) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is the following (1) or (2), or a    pharmaceutically acceptable salt thereof:-   (1)    N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,-   (2)    N-(5-methanesulfonylamino-1,4,6-trimethylindolin-7-yl)-2,2-dimethylpropanamide,-   20) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is any of the following (1)-(6), or    a pharmaceutically acceptable salt thereof:-   (1)    N-(4,6-dimethyl-1-octyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (2)    N-(4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (3)    N-(4,6-dimethyl-1-pentyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (4)    N-[4,6-dimethyl-1-(2-methylpropyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,-   (5)    N-(1-butyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (6)    N-[4,6-dimethyl-1-(3-methylbutyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,-   21) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is any of the following (1)-(7), or    a pharmaceutically acceptable salt thereof:-   (1)    N-(7-methanesulfonylamino-1,4,6-trimethylindolin-5-yl)-2,2-dimethylundecanamide,-   (2)    N-(7-methanesulfonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide,-   (3)    N-[7-(2-propanesulfonylamino)-4,6-dimethylindolin-5-yl]-2,2-dimethylundecanamide,-   (4)    N-[7-(2-propanesulfonylamino)-4,6-dimethylindolin-5-yl]-2,2-dimethyloctanamide,-   (5)    N-[4,6-dimethyl-7-(p-toluene)sulfonylaminoindolin-5-yl]-2,2-dimethylundecanamide,-   (6)    N-(4,6-dimethyl-7-sulfamoylaminoindolin-5-yl)-2,2-dimethylundecanamide,-   (7) N-(4,6-dimethyl-7-ureidoindolin-5-yl)-2,2-dimethylundecanamide,-   22) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is any of the following (1)-(5), or    a pharmaceutically acceptable salt thereof:-   (1)    N-(4,6-dimethyl-5-nitro-1-octylindolin-7-yl)-2,2-dimethylpropanamide,-   (2)    N-(5-methanesulfonylaminomethyl-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide,-   (3)    N-(4,6-dimethyl-1-octyl-5-ureidoindolin-7-yl)-2,2-dimethylpropanamide,-   (4)    N-[5-(N-acetylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide,-   (5)    N-[5-(N-methoxycarbonylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide,-   23) the novel indoline compound of the above-mentioned 9) or 12),    wherein, in the formula (I), R² is —NHSO₂R⁶ (R⁶ is alkyl group), or    a pharmaceutically acceptable salt thereof,-   24) the novel indoline compound of the above-mentioned 9) or 12),    wherein, in the formula (I), R² is —NHSO₂R⁶ [R⁶ is —NHR⁷ (R⁷ is    hydrogen atom)], or a pharmaceutically acceptable salt thereof,-   25) the novel indoline compound of the above-mentioned 2), wherein    the compound of the formula (I) is any-of the following (1)-(6), or    a pharmaceutically acceptable salt thereof:-   (1) N-(1-isopropyl-5-methanesulfonylamino-4,6-dimethylindoline    7-yl)-2,2-dimethylpropanamide,-   (2)    N-[1-(2,2-dimethylpropyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,-   (3)    N-(1-cyclobutylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,-   (4)    N-(1-cyclopentyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,-   (5)    N-(1-cyclopentyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (6)    N-(1-cyclopropylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,-   26) the novel indoline compound of the above-mentioned 3), wherein    the compound of the formula (I) is    N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methyl-2-butenyl)indolin-7-yl]-2,2-dimethylpropanamide,    or a pharmaceutically acceptable salt thereof,-   27) the novel indoline compound of the above-mentioned 3), wherein    the compound of the formula (I) any of the following (1)-(6), or a    pharmaceutically acceptable salt thereof:-   (1)    N-[1-(2-ethoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,-   (2)    N-[1-(2-ethoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,-   (3)    N-[1-(2-methoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,-   (4)    N-[1-(2-methoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,-   (5)    N-[1-(2-ethylthioethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide    hydrochloride,-   (6)    N-[4,6-dimethyl-1-(2-methylthioethyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide    hydrochloride,-   28) the novel indoline compound of the above-mentioned 3), wherein    the compound of the formula (I) is any of the following (1)-(4), or    a pharmaceutically acceptable salt thereof:-   (1)    N-(2-methoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (2)    N-(2-ethoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (3)    N-(2-methylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   (4)    N-(2-ethylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,-   29) the novel indoline compound of the above-mentioned 3), wherein    the compound of the formula (I) is the following (1) or (2), or a    pharmaceutically acceptable salt thereof:-   (1)    N-[1-(2-ethoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,-   (2)    N-[1-(2-methoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,-   30) a pharmaceutical composition comprising a novel indoline    compound of any of the above-mentioned 1)-29), or a pharmaceutically    acceptable salt thereof,-   31) an acyl-coenzyme A: cholesterol acyl transferase inhibitor    comprising a novel indoline compound of any of the above-mentioned    1)-29), or a pharmaceutically acceptable salt thereof,-   32) a lipoperoxidation inhibitor comprising a novel indoline    compound of any of the above-mentioned 1)-29), or a pharmaceutically    acceptable salt thereof, and the like.

MODE OF EMBODIMENTS OF THE INVENTION

Each symbol used in the present specification is explained in thefollowing.

The lower alkyl group for R¹, R² or R¹³ preferably has 1 to 6 carbonatoms and may be linear or branched chain. For example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl and the like can be mentioned.

The lower alkoxy group for R¹ or R³ preferably has 1 to 6 carbon atomsand may be linear or branched chain. For example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like can bementioned.

The lower alkyl group of the lower alkyl group substituted by —NHSO₂R⁶for R² preferably has 1 to 6 carbon atoms and may be linear or branchedchain. For example, methyl, ethyl, propyl, butyl, pentyl, hexyl,1-methylethyl, 1,1-dimethylethyl, 2,2-dimethylpropyl and the like can bementioned. The lower alkyl group is substituted by one —NHSO₂R⁶ at asubstitutable position.

The alkyl group of the alkyl group optionally substituted by hydroxygroup for R⁴ preferably has 1 to 20 carbon atoms, and may be linear orbranched chain. For example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentylhexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosyl,1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylhexyl,1,1-dimethylheptyl, 3,3-dimethylbutyl, 4,4-dimethylpentyl and the likecan be mentioned. The lower alkyl group is substituted by one or twohydroxy groups at substitutable positions.

The lower alkenyl group for R⁴ preferably has 3 to 6 carbon atoms andmay be linear or branched chain. For example, 2-propenyl, 2-butenyl,3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl,3-methyl-2-butenyl and the like can be mentioned.

As for the lower alkoxy lower alkyl group for R⁴ or R¹², its loweralkoxy moiety preferably has 1 to 6 carbon atoms, and may be linear orbranched chain. As the lower alkyl moiety, the lower alkyl groupdescribed above can be mentioned. For example, methoxymethyl,methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,propoxyethyl, isopropoxymethyl, isopropoxyethyl, butoxymethyl,butoxyethyl and the like can be mentioned.

As for the lower alkylthio lower alkyl group for R⁴ or R¹², its alkylmoiety of the lower alkylthio moiety preferably has 1 to 6 carbon atoms,and may be linear or branched chain. As the lower alkyl moiety, thelower alkyl group described above can be mentioned. For example,methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl,ethylthioethyl, ethylthiopropyl, propylthiomethyl, propylthioethyl,isopropylthiomethyl, isopropylthioethyl, butylthiomethyl,butylthioethyl, tert-butylthiomethyl, tert-butylthioethyl,pentylthiomethyl, pentylthioethyl, hexylthiomethyl and the like can bementioned.

The cycloalkyl group for R⁴ or R⁵ preferably has 3 to 8 carbon atoms.For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like can be mentioned.

As for the cycloalkylalkyl group for R⁴, its cycloalkyl moietypreferably has 3 to 8 carbon atoms, and the alkyl moiety preferably has1 to 3 carbon atoms. For example, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,cyclopropylpropyl, cycloheptylmethyl, cyclooctylmethyl and the like canbe mentioned.

The alkyl group for R⁵ or R⁶ preferably has 1 to 20 carbon atoms, andmay be linear or branched chain. For example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentylhexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosyl,1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylhexyl,1,1-dimethylheptyl, 3,3-dimethylbutyl, 4,4-dimethylpentyl and the likecan be mentioned.

As the aryl group for R⁵ or R⁶, for example, phenyl, naphthyl and thelike can be mentioned.

As the lower alkoxycarbonyl group for R⁷, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the likecan be mentioned.

Specific examples of preferable novel indoline compound of the formula(I) includeN-(5-methanesulfonylamino-4,6-dimethyl-1-propylindolin-7-yl)-2,2-dimethylpropanamide,N-[5-methanesulfonylamino-4,6-dimethyl-1-(2-methylpropyl)indolin-7-yl]-2,2-dimethylpropanamide,N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methylbutyl)indolin-7-yl]-2,2-dimethylpropanamide,N-(5-methanesulfonylamino-4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide,N-(5-methanesulfonylamino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide,N-(1-hexyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-(5-methanesulfonylamino-1,4,6-trimethylindolin-7-yl)-2,2-dimethylpropanamide,N-(4,6-dimethyl-1-octyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-(4,16-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-(4,6-dimethyl-1-pentyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-[4,6-dimethyl-1-(2-methylpropyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,N-(1-butyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-[4,6-dimethyl-1-(3-methylbutyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,N-(7-methanesulfonylamino-1,4,6-trimethylindolin-5-yl)-2,2-dimethylundecanamide,N-(7-methanesulfonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide,N-[7-(2-propanesulfonylamino)-4,6-dimethylindolin-5-yl]-2,2-dimethylundecanamide,N-[7-(2-propanesulfonylamino)-4,6-dimethylindolin-5-yl]-2,2-dimethyloctanamide,N-[4,6-dimethyl-7-(p-toluene)sulfonylaminoindolin-5-yl]-2,2-dimethylundecanamide,N-(4,6-dimethyl-7-sulfamoylaminoindolin-5-yl)-2,2-dimethylundecanamide,N-(4,6-dimethyl-7-ureidoindolin-5-yl)-2,2-dimethylundecanamide,N-(4,6-dimethyl-5-nitro-1-octylindolin-7-yl)-2,2-dimethylpropanamide,N-(5-methanesulfonylaminomethyl-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide,N-(4,6-dimethyl-1-octyl-5-ureidoindolin-7-yl)-2,2-dimethylpropanamide,N-[5-(N-acetylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide,N-[5-(N-methoxycarbonylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide,N-(1-isopropyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-[1-(2,2-dimethylpropyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,N-(1-cyclobutylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-(1-cyclopentyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methyl-2-butenyl)indolin-7-yl]-2,2-dimethylpropanamide,N-(1-cyclopentyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-(1-cyclopropylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,N-[1-(2-ethoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,N-[1-(2-ethoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,N-[1-(2-methoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,N-[1-(2-methoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,N-[1-(2-ethylthioethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride,N-[4,6-dimethyl-1-(2-methylthioethyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride,N-(2-methoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-(2-ethoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-(2-methylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-(2-ethylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,N-[1-(2-ethoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,N-[1-(2-methoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamideand the like, or a pharmaceutically acceptable salt thereof.

The compound (I) may form a pharmaceutically acceptable salt. Whencompound (I) has a basic group, an acid addition salt can be formed,wherein an acid to form an acid addition salt is free of particularlimitation, as long as it can form a salt with a basic moiety and ispharmaceutically acceptable. As such acid, inorganic acids such ashydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and thelike, and organic acids such as oxalic acid, fumaric acid, maleic acid,citric acid, tartaric acid, methanesulfonic acid, toluenesulfonic acidand the like can be mentioned.

The novel indoline compound (I) and a pharmaceutically acceptable saltthereof of the present invention can be produced by any of the followingproduction methods.

wherein R¹, R³ and R⁵ are each as defined above, R^(4a) is alkyl group,cycloalkyl group, cycloalkylalkyl group or lower alkoxy lower alkylgroup, R⁸ is amino protecting group, R⁹ is alkyl group or aryl group,R^(12a) is hydrogen atom, lower alkyl group or lower alkoxy lower alkylgroup and X is a leaving group such as halogen atom (chlorine atom,bromine atom or iodine atom), alkanesulfonyloxy (e.g.,methanesulfonyloxy, ethanesulfonisoxy, propanesulfonyloxy ortrifluoromethanesulfonyloxy etc.) or arylsulfonyloxy (e.g.,phenylsulfonyloxy or tolylsulfonyloxy etc.) and the like.

In Production Method 1, novel indoline compound (Ia) and (Ib), whereinR² is —NO₂ or —NHSO₂R⁹ (R⁹ is alkyl group or aryl group), are produced.

As the amino protecting group for R⁸, for example, formyl, acetyl,monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl,methoxymethylcarbonyl, methoxymethyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl,tert-butoxycarbonyl (hereinafter to be referred to as Boc), benzyl,trimethylsilyl, trityl and the like can be mentioned.

The compound (III) wherein R^(12a) is hydrogen atom can be produced byreducing compound (II) wherein R^(12a) is hydrogen atom [J. EricNordlander, et al., J. Org. Chem., 46, 778-782 (1981), Robin D. Clark,et al., Heterocycle, 22, 195-221 (1984), Vernon H. Brown, et al., J.Heterocycle. Chem., 6(4), 539-543 (1969)] to convert to an indolineskeleton, and then protecting the amino group.

The compound (III) wherein R^(12a) is lower alkyl group can be producedfrom compound (II) wherein R^(12a) is lower alkyl group [Beil 20, 311]by similar steps as mentioned above.

The compound (III) wherein R^(12a) is lower alkoxy lower alkyl group canbe produced by the method shown in Production Method 1-a.

wherein R¹, R³ and R⁸ are each as defined above, R^(12a) is lower alkoxylower alkyl group, and A is lower alkylene group.

The compound (III) wherein R^(12a) is lower alkoxy lower alkyl group canbe produced by reducing compound (IIa) [Christopher A. Demerson, et al.,J. Med. Chem., 19, 391-395 (1976), Gilbverto Spadoni, et al., J. Med.Chem., 41, 3624-3634 (1998)] to give indoline compound, protecting aminogroup to give compound (IIb), and then alkylating hydroxy group by amethod known per se.

The compound (IV) of Production Method 1 can be produced by introducingnitro group onto a benzene ring of compound (III) by a method known perse and reducing the nitro group using a catalyst such aspalladium-carbon and the like.

The compound (VI) can be produced by reacting compound (IV) withcompound (V) or reactive derivative thereof at carboxyl group.

This reaction is generally carried out in an inert solvent. As the inertsolvent, acetone, dioxane, acetonitrile, chloroform, benzene, methylenechloride, ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine, water and the like, a mixture of theseand the like can be specifically mentioned. In addition, a base such astriethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonateand the like can be used.

The reaction temperature is generally −10° C. to 160° C., preferably 0°C. to 60° C., and the reaction time is generally 30 min to 10 hr.

The compound (V) is used for this reaction as a free carboxylic acid, oras a reactive derivative thereof, and both embodiments are encompassedin this reaction. To be specific, it is subjected to this reaction as afree acid or a salt such as sodium, potassium, calcium, triethylamine,pyridine and the like, or a reactive derivative thereof such as an acidhalide (acid chloride, acid bromide etc.), an acid anhydride, a mixedacid anhydride [substituted phosphoric acid (dialkylphosphoric acidetc.), an alkyl carbonate (monoethyl carbonate etc.) and the like], anactive amide (amide with imidazole and the like), an ester (cyanomethylester, 4-nitrophenyl ester etc.) and the like.

In this reaction, when compound (V) is used in the form of a free acidor salt, the reaction is preferably carried out in the presence of acondensing agent. As the condensing agent, for example, dehydratingagents such as N,N′-disubstituted carbodiimides (e.g.,N,N′-dicyclohexylcarbodiimide etc.); carbodiimide compounds (e.g.,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide,N-cyclohexyl-N′-morpholinoethylcarbodiimide,N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide etc.); azolidecompounds (e.g., N,N′-carbonyldiimidazole, N,N′-thionyldiimidazole etc.)and the like are used. When these condensing agents are used, thereaction is considered to proceed via a reactive derivative ofcarboxylic acid.

The compound (VIII) can be produced by nitrating compound (VI) by amethod known per se to give compound (VII), and eliminating the aminoprotecting group for R⁸ from the obtained compound (VII).

The amino protecting group can be eliminated by a method known per se,and as the elimination method, depending on the kind of the protectinggroup, for example, a method comprising treatment with an acid(hydrochloric acid, trifluoroacetic acid etc.) when, for example, it isformyl, tert-butoxycarbonyl, trityl and the like, a method comprisingtreatment with a base (sodium hydroxide, potassium hydroxide, sodiumcarbonate, sodium bicarbonate etc.), when, for example, it is acetyl,dichloroacetyl, trifluoroacetyl and the like, a method comprisingcatalytic reduction using palladium-carbon and the like as a catalystwhen, for example, it is benzyl, benzyloxycarbonyl and the like, and thelike can be mentioned.

The compound (Ia) can be produced by reacting compound (VIII) withcompound (IX).

This reaction is carried out in a solvent that does not inhibit thereaction, such as acetone, dioxane, acetonitrile, tetrahydrofuran,chloroform, methylene chloride, ethylene chloride, benzene, toluene,xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide,dimethyl sulfoxide, pyridine, water and the like, and a mixture ofthese, in the presence of a base.

The molar ratio of compound (VIII) and compound (IX) to be used is notparticularly limited, and 1 to 5 mol, preferably 1 to 3 mol, of compound(IX) is preferably used, per 1 mol of compound (VIII).

The base to be used for this reaction is not particularly limited, andinorganic bases such as alkali metal carbonates (e.g., sodium carbonate,sodium hydrogencarbonate, potassium carbonate, potassiumhydrogencarbonate and the like), alkali metal hydroxides (e.g., sodiumhydroxide, potassium hydroxide and the like) and the like, and organicbases such as alkali metal alcoholates (e.g., sodium methoxide, sodiumethoxide, potassium-tert-butoxide and the like), metal hydride compounds(e.g., sodium hydride, potassium hydride, calcium hydride and the like),triethylamine, diisopropylethylamine and the like can be mentioned.

The reaction temperature is generally −10° C. to 100° C., preferably 0°C. to 60° C., and the reaction time is generally 30 min to 10 hr.

The compound (Ib) can be produced by reducing nitro group of compound(Ia) by a method known per se to give compound (X) and reacting theobtained compound (X) with compound (XI).

The reaction between compound (X) and compound (XI), is carried out in asolvent that does not inhibit the reaction, such as acetone, dioxane,acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylenechloride, benzene, toluene, xylene, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide,pyridine, water and the like, or a mixture of these, in the presence ofa base.

The molar ratio of compound (X) and compound (XI) to be used is notparticularly limited, and 1 to 5 mol, preferably 1 to 3 mol, of compound(XI) is preferably used per 1 mol of compound (X).

The base to be used for this reaction is not particularly limited, andinorganic bases such as alkali metal carbonates (e.g., sodium carbonate,sodium hydrogencarbonate, potassium carbonate, potassiumhydrogencarbonate and the like), alkali metal hydroxides (e.g., sodiumhydroxide, potassium hydroxide and the like) and the like, and organicbases such as alkali metal alcoholates (e.g., sodium methoxide, sodiumethoxide, potassium-tert-butoxide and the like), metal hydride compounds(e.g., sodium hydride, potassium hydride, calcium hydride and the like),triethylamine, diisopropylethylamine and the like can be mentioned.

The molar ratio of compound (X) and base to be used is not particularlylimited, and 1 to 5 mol, preferably 1 to 3 mol, of base is preferablyused per 1 mol of compound (X).

While the reaction conditions such as reaction temperature, reactiontime and the like vary depending on the reaction reagent, reactionsolvent and the like to be used, the reaction is carried out generallyat −30° C. to 150° C. for 30 min to several dozen hours.

wherein R¹, R³, R^(4a), R⁵ and R^(12a) are each as defined above and R¹⁰is lower alkyl group or lower alkoxy group.

In Production Method 2, novel indoline compounds (Ic) and (Id) whereinR² is —NHSO₂NHCOR¹⁰ (R¹⁰ is lower alkyl group or lower alkoxy group) or—NHSO₂NH₂ are produced.

The compound (Ic) can be produced by reacting compound (X) with compound(XII).

This reaction is carried out in a solvent that does not inhibit thereaction, such as acetone, dioxane, acetonitrile, tetrahydrofuran,chloroform, methylene chloride, ethylene chloride, benzene, toluene,xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide,dimethyl sulfoxide, pyridine, water and the like, or a mixture of these,in the presence of a base.

The molar ratio of compound (X) and compound (XII) to be used is notparticularly limited, and 1 to 5 mol, preferably 1 to 3 mol, of compound(XII) is preferably used per 1 mol of compound (X).

The base to be used for this reaction is not particularly limited, andinorganic bases such as alkali metal carbonates (e.g., sodium carbonate,sodium hydrogencarbonate, potassium carbonate, potassiumhydrogencarbonate and the like), alkali metal hydroxides (e.g., sodiumhydroxide, potassium hydroxide and the like) and the like, and organicbases such as alkali metal alcoholates (e.g., sodium methoxide, sodiumethoxide, potassium-tert-butoxide and the like), metal hydride compounds(e.g., sodium hydride, potassium hydride, calcium hydride and the like),triethylamine, diisopropylethylamine and the like can be mentioned.

The reaction temperature is generally −10° C. to 100° C., preferably 0°C. to 60° C. and the reaction time is generally 30 min to 10 hr.

The compound (Id) can be produced by hydrolyzing —COR¹⁰ group ofcompound (Ic) by a method known per se under acidic or alkalinecondition.

wherein R¹, R³, R^(4a), R⁵ and R^(12a) are each as defined above.

In Production Method 3, novel indoline compound (Ie) wherein R² is—NHCONH₂ is produced.

The compound (Ie) can be produced from compound (X) according to generalsynthetic methods of ureas such as addition reaction with isocyanatessuch as cyanic acid, chlorosulfonyl isocyanate and the like,condensation reaction with urea and the like [S. R. Sandler, W. Karo,“Organic Functional Group Preparation”, Vol. 2, Academic Press (1971),Chapt. 6].

wherein R¹, R³, R^(4a), R⁵, R⁸, R⁹, R^(12a) and X are each as definedabove, R¹¹ is amino protecting group, and A is lower alkylene group.

In Production Method 4, novel indoline compound (If) wherein R² is loweralkyl group substituted by —NHSO₂R⁹ (R⁹ is alkyl group or aryl group) isproduced.

Compound (XIII) having halogenomethyl group can be produced bysubjecting compound (VI) to halogenomethylation [R. C. Fuson. et al.,Org. React., 1,63 (1969), G. A. Olah. et al., “Friedel Crafts andRelated Reaction” Vol. 2, 659 (1964)], and compound (XIII) havinghalogenoethyl group can be produced by converting halogen atom of theintroduced halogenomethyl group to cyano group by a method known per seand hydrolyzing the cyano group to convert to carboxyl group oralkoxycarbonyl group, reducing the obtained carboxyl group oralkoxycarbonyl group by a method known per se to give an alcohol formand halogenating hydroxy group of the alcohol form. By repeating thisstep, compounds (XIII) having halogenopropyl group, halogenobutyl groupand the like can be respectively produced.

The compound (XIV) can be produced by introducing amino group intocompound (XIII) by a substituent conversion reaction known per se andprotecting the amino group thereof. In this stage, compound (XIV)wherein both R⁸ and R¹¹ are amino protecting groups is obtained. As R⁸and R¹¹, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl,methoxymethylcarbonyl, methoxymethyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl, Boc,benzyl, trimethylsilyl, trityl and the like are used. It is essentialthat R⁸ and R¹¹ are different and selectively eliminatable aminoprotecting groups.

The compound (XVI) can be produced from compound (XIV) by a methodsimilar to the method of producing compound (Ia) from the compound (VII)via compound (VIII) in Production Method 1.

The compound (XVII) can be produced by eliminating the amino protectinggroup R¹¹ of compound (XVI) by a method known per se.

The compound (If) can be produced from compound (XVII) by a methodsimilar to the method of producing compound (Ib) by reacting compound(X) with compound {XI) in Production Method 1.

wherein R¹, R³, R^(4a), R⁵, R¹⁰, R^(12a) and A are each as definedabove.

In Production Method 5, novel indoline compounds (Ig) and (Ih) whereinR² is —NHSO₂NHCOR¹⁰ (R¹⁰ is lower alkyl group or lower alkoxy group) orlower alkyl group substituted by —NHSO₂NH₂ are produced.

The compounds (Ig) and (Ih) can be produced from compound (XVII) by amethod similar to Production Method 2.

wherein R¹, R³, R^(4a), R^(12a) and A are each as defined above.

In production method 6, novel indoline compound (Ii) wherein R² is loweralkyl group substituted by —NHCONH₂ is produced.

The compounds (Ii) can be produced from compound (XVII) by a methodsimilar to Production Method 3.

wherein R¹, R³, R⁵, R⁸, R⁹ and R^(12a) are as defined above.

In Production Method 7, novel indoline compound (Ij) wherein R² is—NHSO₂R⁹ (R⁹ is alkyl group or aryl group) and R⁴ is hydrogen atom isproduced.

The compound (XIX) can be produced from compound (VII) by a methodsimilar to the method of producing compound (Ib) from compound (Ia) viacompound (X) in Production Method 1.

The compound (Ij) can be produced by eliminating the amino protectinggroup R⁸ of compound (XIX) by a method known per se.

wherein R¹, R³, R⁵, R⁸, R¹⁰ and R^(12a) are as defined above.

In Production Method 8, novel indoline compounds (Ik) and (II) whereinR² is —NHSO₂NHCOR¹⁰ (R¹⁰ is lower alkyl group or lower alkoxy group) or—NHSO₂NH₂ and R⁴ is hydrogen atom are produced.

The compound (XX) can be produced from compound (XVIII) by a methodsimilar to the method of producing compound (Ic) from compound (X) inProduction Method 2.

The compound (Ik) can be produced by eliminating the amino protectinggroup R⁸ of compound (XX) by a method known per se.

The compound (II) can be produced by hydrolyzing the —COR¹⁰ group ofcompound (Ik) under acidic or alkaline condition by a method known perse.

wherein R¹, R³, R⁵, R⁹ and R^(12a) are as defined above, and R^(4b) isalkyl group, cycloalkyl group, cycloalkylalkyl group, lower alkenylgroup or lower alkoxy lower alkyl group.

In Production Method 9, a novel indoline compound (Ib′) is produced fromcompound (Ij).

The compound (Ib′) can be produced by a method similar to the method ofproducing compound (Ia) by reacting compound (VIII) with compound (IX)in Production Method 1.

wherein R¹, R³, R^(4b), R⁵, R¹⁰ and R^(12a) are as defined above.

In Production Method 10, novel indoline compounds (Ic′) and (Id′) areproduced from compound (Ik).

The compound (Ic′) can be produced by a method similar to the method ofproducing compound (Ia) by reacting compound (VIII) with compound (IX)in Production Method 1 in the same manner as in Production Method 9.

The compound (Id′) can be produced by hydrolyzing the —COR¹⁰ group ofcompound (Ic′) under acidic or alkaline condition by a method known perse.

wherein R¹, R³, R⁵, R⁹ and R^(12a) are as defined above, and R¹³ ishydrogen atom or lower alkyl group.

In Production Method 11, novel indoline compound (Im) wherein R² is—NHSO₂R⁹ (R⁹ is alkyl group or aryl group) and R⁴ is —COR¹³ (R¹³ ishydrogen atom or lower alkyl group) is produced.

The compound (XXII) can be produced from compound (VIII) and compound(XXI) by a method similar to the method of producing compound (VI) fromthe compound (IV) in Production Method 1.

The compound (Im) can be produced from compound (XXII) by a methodsimilar to the method of producing compound (Ib) from the compound (Ia)via compound (X) in Production Method 1.

wherein R¹, R³, R⁵, R⁸, R¹⁰, R^(12a) and R¹³ are as defined above.

In Production Method 12, novel indoline compounds (In) and (Io) wherein,in the formula (I), R² is —NHSO₂NHCOR¹⁰ (R¹⁰ is lower alkyl group orlower alkoxy group) or —NHSO₂NH₂, and R⁴ is —COR¹³ (R¹³ is hydrogen atomor lower alkyl group) are produced.

The compound (In) can be produced from compound (Ik) and compound (XXI)by a method similar to the method of producing compound (VI) from thecompound (IV) in Production Method 1 in the same manner as in ProductionMethod 11.

The compound (Io) can be produced by hydrolyzing the —COR¹⁰ group ofcompound (In) under acidic or alkaline condition by a method known perse.

wherein R¹, R³, R^(4a), R⁵ and A are as defined above, R¹⁴ is hydroxyprotecting group, R¹⁵ is lower alkyl group and B is oxygen atom orsulfur atom.

In Production Method 13, compound (XXVI), which is an intermediate forproducing novel indoline compound (I) wherein R¹² is lower alkoxy loweralkyl group or lower alkylthio lower alkyl group, is produced.

As the hydroxy protecting group for R¹⁴, for example, ethers and acetalssuch as methyl ether, isopropyl ether, tert-butyl ether, benzyl ether,allyl ether, methoxymethyl ether, tetrahydropyranyl ether,p-bromophenacyl ether, trimethylsilyl ether and the like, esters such asformyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl,methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoyl,methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like, andthe like can be mentioned.

The compound (IVa) can be produced by protecting the hydroxy group ofcompound (IIb) by a method known per se to give compound (IIIa), and bya method similar to the method of producing compound (IV) from thecompound (III) in Production Method 1.

The compound (XXIV) can be produced from compound (IVa) by a methodsimilar to the method of producing compound (Ia) from the compound (IV)in Production Method 1.

The compound (XXV) can be produced by eliminating the hydroxy protectinggroup R¹⁴ of compound (XXIV). While the method of eliminating a hydroxyprotecting group varies depending on the kind thereof, generally, amethod known per se as the technique in this field can be used for theelimination.

The compound (XXVI) wherein -A-B—R¹⁵ is lower alkoxy lower alkyl groupor lower alkylthio lower alkyl can be produced by a method known per se,which comprises converting the hydroxy group of compound (XXV) to aleaving group such as halogen atom (chlorine atom, bromine atom oriodine atom), alkanesulfonyloxy (e.g., methanesulfonyloxy,ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxyetc.), arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy etc.)and the like, and reacting the compound with lower alcohol or loweralkylthiol compound in the presence of a base.

In addition, compound (XXVI) wherein -A-B—R¹⁵ is lower alkoxy loweralkyl group can be also produced by a method known per se, whichcomprises reacting compound (XXV) with R⁵—X (compound (XXVII)) whereinR¹⁵ and X are as defined above.

Moreover, compound (XXVI) wherein -A-B—R¹⁵ is lower alkylthio loweralkyl group can be also produced by converting the hydroxy group ofcompound (XXV) to thiol group by a method known per se and reacting thecompound with compound (XXVII).

The compound (XXVI) produced by Production Method 13 is used as anintermediate in Production Method 1-3 or Production Method 7-12 and canproduce the corresponding novel indoline compound (I).

wherein R¹, R³, R⁵, R^(12a), R¹⁵, X, A and B are as defined above andR¹⁶ is hydrogen atom or hydroxy protecting group.

In Production Method 14, compound (XXXI), which is an intermediate forproducing novel indoline compound (I) wherein R⁴ is lower alkoxy loweralkyl group or lower alkylthio lower alkyl group, is produced.

The compound (XXIX) can be produced from compound (VIII) and compound(XXVIII) by a method similar to the method of producing compound (Ia)from the compound (VIII) and compound (IX) in Production Method 1.

When R¹⁶ is hydroxy protecting group, compound (XXX) can be produced byeliminating the hydroxy protecting group R¹⁶ of compound (XXIX) by amethod known per se.

In addition, compound (XXX) can be also produced from compound (VIII)and compound (XXVIII) wherein R¹⁶ is hydrogen atom.

The compound (XXXI) can be produced from compound (XXX) by a methodsimilar to the method of producing compound (XXVI) from the compound(XXV) in Production Method 13.

The compound (XXXI) produced by Production Method 14 is used as anintermediate in Production Methods 1-3 or Production Methods 7-12 andproduces the corresponding novel indoline compound (I).

wherein R¹⁰ is as defined above.

In Production Method 15, compound (XII) to be used for ProductionMethods 2, 5 and 8 is produced.

The compound (XII) can be produced from chlorosulfonyl isocyanate by amethod known per se, or reacted with lower carboxylic acid to givecompound (XII) wherein R¹⁰ is lower alkyl group, and reacted with loweralcohol to give compound (XII) wherein R¹⁰ is lower alkoxy group.

When R¹², which is a substituent at the 5-membered ring of the indolineskeleton of compound (I), is lower alkyl group, lower alkoxy lower alkylgroup or lower alkylthio lower alkyl group, the carbon atom substitutedby R¹² becomes an asymmetric carbon. In this case, compound (I) containsstereoisomers based on the asymmetric carbon, which are also encompassedin the present invention.

The compound of the present invention (I) obtained as mentioned abovecan be purified by conventionally known methods (e.g., chromatography,recrystallization etc.).

Moreover, compound (I) can be converted to a pharmaceutically acceptablesalt thereof by a method known per se.

While the dose of compound (I) and a pharmaceutically acceptable saltthereof of the present invention varies depending on the subject ofadministration, conditions, and other factors, when orally administeredto, for example, adult patients with hypercholesterolemia, a single doseof 0.1 mg to 50 mg/kg body weight can be administered about 1 to 3 timesa day.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, which are not to be construed as limitative.

Example 1N-(4,6-dimethyl-5-nitro-1-octylindolin-7-yl)-2,2-dimethylpropanamide

-   (1) 4,6-Dimethylindole (160 g) was dissolved in acetic acid (800    mL), and sodium cyanoborohydride (138 g) was added in portions under    ice-cooling over 1 hr. The mixture was stirred at the same    temperature for 2 hr. The reaction solution was poured into ice    water (3 L) and ethyl acetate (2 L) was added. The mixture was    neutralized with aqueous sodium hydroxide solution at not more than    20° C. and the aqueous layer was saturated with sodium chloride. The    ethyl acetate layer was separated and dried over sodium sulfate, and    ethyl acetate was evaporated under reduced pressure. The obtained    residue was dissolved in benzene (600 mL) and acetic anhydride    (135 g) was added. The mixture was stirred at room temperature for 1    hr and the precipitated crystals were collected by filtration. The    solvent of the filtrate was evaporated under reduced pressure, and    the residue was dissolved in chloroform, washed successively with    saturated aqueous sodium hydrogencarbonate and saturated brine, and    dried over sodium sulfate. Chloroform was evaporated under reduced    pressure and the residue was combined with the crystals obtained    earlier to give 1-acetyl-4,6-dimethylindoline as crystals (208 g).

IR ν (Nujol) cm⁻¹; 1655, 1595.

¹H-NMR (CDCl₃) δ (ppm); 2.18 (6H, s), 2.30 (3H, s), 3.00 (2H, t, J=8.5Hz), 4.03 (2H, t, J=8.5 Hz), 6.66 (1H, s), 7.89 (1H, s).

-   (2) The compound (200 g) obtained in (1) was dissolved in acetic    acid (4 L) and bromine (85 mL) was added dropwise under ice-cooling.    The mixture was stirred at room temperature for 30 min. The reaction    solution was poured into ice water (20 L), sodium hydrogensulfite    (5 g) was added, and the mixture was stirred for 30 min. The    precipitated crystals were collected by filtration, dissolved in    chloroform (2 L), washed successively with water and saturated brine    and dried over sodium sulfate. Chloroform was evaporated under    reduced pressure and the obtained crystalline residue was    recrystallized from methanol to give    1-acetyl-5-bromo-4,6-dimethylindoline as white crystals (185 g).

IR ν (Nujol) cm⁻¹; 1660.

¹H-NMR (CDCl₃) δ (ppm); 2.19 (3H, s), 2.27 (3H, s), 2.39 (3H, s), 3.06(2H, t, J=8.5 Hz), 4.03 (2H, t, J=8.5 Hz), 7.99 (1H, s).

-   (3) To a mixture of fumed nitric acid (44 mL), acetic acid (500 mL)    and concentrated sulfuric acid (500 mL) was added the compound    (185 g) obtained (2) in portions at −5 to 0° C. over 1 hr, and the    mixture was stirred under ice-cooling for 3 hr. The reaction    solution was poured into ice water (6 L), and the precipitated    crystals were collected by filtration. The obtained crystals were    dissolved in chloroform (3 L), washed successively with water and    saturated brine and dried over sodium sulfate. Chloroform was    evaporated under reduced pressure to give    1-acetyl-5-bromo-4,6-dimethyl-7-nitroindoline as crystals (209 g).

IR ν (Nujol) cm⁻¹; 1672, 1654.

¹H-NMR (CDCl₃) δ (ppm); 2.20 (3H, s), 2.35 (3H, s), 2.45 (3H, s), 3.12(2H, t, J=8.5 Hz), 4.16 (2H, t, J=8.5 Hz).

-   (4) The compound (75 g) obtained in (3) was dissolved in a mixture    (1 L) of chloroform-methanol (1:1). 5% Palladium-carbon (10 g) was    added, and the mixture was subjected to catalytic hydrogenation at    40° C. for 2 days at ordinary pressure. Partly precipitated    1-acetyl-7-amino-4,6-dimethylindoline bromate was filtered off    together with palladium-carbon and the obtained solid was    neutralized with saturated aqueous sodium hydrogencarbonate, and    extracted with chloroform (0.5 L). The solvent in the filtrate was    evaporated under reduced pressure and the residue was similarly    neutralized with saturated aqueous sodium hydrogencarbonate and    extracted with chloroform (1 L). The extract was combined with the    chloroform layer mentioned earlier, washed with saturated brine and    dried over sodium sulfate, and chloroform was evaporated under    reduced pressure. The obtained residue was dissolved in chloroform    (300 mL). Pivaloyl chloride (27.7 g) was added and triethylamine    (29.1 g) was added dropwise at not more than 20° C., and the mixture    was stirred at room temperature for 1 hr. Chloroform (1 L) was added    and the mixture was washed successively with 5% aqueous citric acid    and saturated brine (each 500 mL) and dried over sodium sulfate.    Chloroform was evaporated under reduced pressure and n-hexane (200    mL) was added to the obtained crystalline residue. The crystals were    washed by stirring the mixture and filtered to give    N-(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide as    crystals (49 g).

IR ν (Nujol) cm⁻¹; 1677, 1639.

¹H-NMR (CDCl₃) δ (ppm); 1.27 (9H, s), 2.17 (6H, s), 2.29 (3H, s), 2.94(2H, t, J=8.5 Hz), 4.09 (2H, t, J=8.5 Hz), 6.87 (1H, s), 9.09 (1H,br-s).

-   (5) The compound (1.99 g) obtained in (4) was dissolved in acetic    acid (20 mL) and fumed nitric acid (0.41 mL) was added dropwise    under ice-cooling. The mixture was stirred at 50° C. for 4 hr and    the reaction mixture was poured into ice water. The precipitated    crystals were collected by filtration, and the obtained crystals    were dissolved in chloroform (300 mL). The solution was washed    successively with saturated aqueous sodium hydrogencarbonate and    saturated brine and dried over sodium sulfate. Chloroform was    evaporated under reduced pressure and the obtained residue was    purified by silica gel column chromatography to give    N-(1-acetyl-4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    (2.2 g).

IR ν (Nujol) cm⁻¹; 1670, 1641, 1583, 1528.

¹H-NMR (CDCl₃) δ (ppm); 1.27 (9H, s), 2.11 (3H, s), 2.15 (3H, s), 2.32(3H, s), 3.04 (2H, t, J=8.0 Hz), 4.16 (2H, t, J=8.0 Hz), 9.07 (1H,br-s).

-   (6) The compound (0.8 g) obtained in (5) was dissolved in methanol    (8 mL) and 4M aqueous sodium hydroxide solution (3 mL) was added.    The mixture was stirred at 80° C. for 15 min. The solvent was    evaporated under reduced pressure and the obtained residue was    dissolved in chloroform (50 mL). The solution was washed    successively with water and saturated brine and dried over sodium    sulfate. The obtained residue was purified by silica gel column    chromatography to give    N-(4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide (0.68    g).

IR ν (Nujol) cm⁻¹; 1643, 1597, 1508.

¹H-NMR (CDCl₃) δ (ppm); 1.35 (9H, s), 2.14 (3H, s), 2.16 (3H, s), 3.01(2H, t, J=8.5 Hz), 3.67 (2H, t, J=8.5 Hz), 4.26 (1H, br), 7.03 (1H,br-s).

-   (7) The compound (3.5 g) obtained in (6) was dissolved in    N,N-dimethylformamide (40 mL) and sodium hydride (60% oil    suspension) (576 mg) was added in portions under a nitrogen    atmosphere and under ice-cooling. After stirring at room temperature    for 10 min, octyl iodide (2.6 mL) was added and the mixture was at    the same temperature for 17 hr. Water (100 mL) was added and the    mixture was extracted with diethyl ether (300 mL). The diethyl ether    layer was washed successively with water and saturated brine and    dried over sodium sulfate. The obtained residue was purified by    silica gel column chromatography to give the title compound as    crystals (3.2 g).

IR ν (Nujol) cm⁻¹; 1649, 1597, 1560, 1516.

¹H-NMR (CDCl₃) δ (ppm); 0.88 (3H, br-t), 1.08-1.51 (12H, m), 1.33 (9H,s), 2.03 (3H, s), 2.10 (3H, s), 2.86 (2H, t), 3.23 (2H, br-t), 3.54 (2H,t, J=8.5 Hz), 6.74 (1H, br-s).

Example 2N-(5-methanesulfonylamino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide

The compound (3.2 g) obtained Example 1 was dissolved in a mixture (120mL) of methanol-toluene (3:1) and 5% palladium-carbon (0.48 g) wasadded. The mixture was subjected to catalytic hydrogenation at roomtemperature and 2 kgf/cm² for 17 hr. Palladium-carbon was filtered offand the solvent was evaporated under reduced pressure. The obtainedresidue was dissolved in chloroform (300 mL), washed with saturatedbrine and dried over sodium sulfate. Chloroform was evaporated underreduced pressure and the obtained residue was dissolved in chloroform(30 mL). Triethylamine (3.32 mL) was added, methanesulfonyl chloride(1.23 mL) was added dropwise under ice-cooling, and the mixture wasstirred at room temperature for 3 hr. Chloroform (100 mL) was added,washed successively with 5% aqueous citric acid, water and saturatedbrine and dried over sodium sulfate. Chloroform was evaporated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography to give the title compound as crystals (3.0 g).

IR ν (Nujol) cm⁻¹; 3358, 1665, 1597, 1502.

¹H-NMR (CDCl₃) δ (ppm); 0.88 (3H, br-t), 1.18-1.58 (12H, m), 1.34 (9H,s), 2.10 (3H, s), 2.15 (3H, s), 2.86 (2H, t, J=8.3 Hz), 2.97 (3H, s),3.15 (2H, br-t), 3.24 (2H, t, J=8.3 Hz), 6.10 (1H, br), 6.85 (1H, br-s).

Example 3N-[5-(N-acetylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide

-   (1) Chlorosulfonyl isocyanate (3.04 mL) was added dropwise to acetic    acid (2.0 mL) under ice-cooling and n-hexane was added. The    precipitated crystals were collected by filtration to give    acetylsulfamoyl chloride as crystals (5.31 g).-   (2) The compound (3.0 g) obtained in Example 1 was dissolved in a    mixture (110 mL) of methanol-toluene (3:1), and 5% palladium-carbon    (0.45 g) was added. The mixture was subjected to catalytic    hydrogenation at room temperature and 2 kgf/cm² for 17 hr.    Palladium-carbon was filtered off, and the solvent was evaporated    under reduced pressure. The obtained residue was dissolved in    chloroform (300 mL). The solution was washed with saturated brine    and dried over sodium sulfate. Chloroform was evaporated under    reduced pressure. The obtained residue    (N-(5-amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide)    (2.67 g) was dissolved in chloroform (27 mL) and triethylamine (1.2    mL) and the compound (2.25 g) obtained in (1) were added at −10° C.    The mixture was stirred at room temperature for 30 min. 10% Aqueous    citric acid was added to the reaction mixture and the mixture was    extracted with chloroform (100 mL). The chloroform layer was washed    successively with saturated aqueous sodium hydrogencarbonate and    saturated brine and dried over sodium-sulfate. Chloroform was    evaporated under reduced pressure and the obtained residue was    purified by silica gel column chromatography. The obtained crystals    were recrystallized from toluene (50 mL) to give the title compound    as crystals (1.84 g).

IR ν (Nujol) cm⁻¹; 3302, 1701, 1649, 1163.

¹H-NMR (CDCl₃) δ (ppm); 0.88 (3H, br-t), 1.00-1.70 (12H, m), 1.29 (9H,s), 1.93 (3H, s), 1.97 (3H, s), 2.08 (3H, s), 2.77 (2H, t, J=8.2 Hz),3.14 (2H, t, J=4.5 Hz), 3.40 (2H, t, J=8.2 Hz), 5.00 (1H, br-s), 6.80(1H, br-s), 7.09 (1H, s).

Example 4N-[5-(N-methoxycarbonylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide

Methanol (0.13 mL) was added to methylene chloride (2.6 mL) andchlorosulfonyl isocyanate (0.29 mL) was added at −20° C. The mixture wasstirred at −20° C. to 10° C. for 20 min.N-(5-Amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide(612 mg) and triethylamine (0.46 mL) were added to the reaction mixtureand the mixture was further stirred at −9° C. for 30 min. Methylenechloride was added to the reaction mixture, and the mixture was washedsuccessively with 10% aqueous citric acid, saturated aqueous sodiumhydrogencarbonate and saturated brine and dried over sodium sulfate.Methylene chloride was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound as crystals. (601 mg).

IR ν (Nujol) cm⁻¹; 3300, 1736, 1655, 1597.

¹H-NMR (CDCl₃) δ (ppm); 0.87 (3H, br-t), 1.00-1.60 (12H, m), 1.95 (3H,s), 2.10 (3H, s), 2.77 (2H, t, J=8.0 Hz), 3.15 (2H, br-t), 3.42 (2H, t,J=8.0 Hz), 3.78 (3H, s), 6.70 (1H, br-s), 7.03 (1H, br-s), 7.26 (1H,br-s).

Example 5N-[5-(N-tert-butoxycarbonylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide

tert-Butanol (0.85 mL) was dissolved in methylene chloride (17 mL) andchlorosulfonyl isocyanate (0.77 mL) was added at −18° C. The mixture wasstirred at the same temperature for 30 min andN-(5-amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide(1.66 g) and triethylamine (1.24 mL) were added. The mixture was furtherstirred at −5° C. for 30 min. Methylene chloride (50 mL) was added, andthe mixture was washed successively with 10% aqueous citric acid,saturated aqueous sodium hydrogencarbonate, and then saturated brine (50mL) and dried over sodium sulfate. Then, methylene chloride wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give the title compound as crystals(1.9 g).

IR ν (Nujol) cm⁻¹; 3371, 3167, 1755, 1728, 1655, 1597.

¹H-NMR (DMSO-d₆) δ (ppm); 0.88 (3H, br-t), 1.05-1.80 (21H, m), 1.49 (9H,s), 1.98 (3H, s), 2.14 (3H, s), 2.78 (2H, br-t), 3.17 (2H, br-t), 3.39(2H, br-t), 6.69 (1H, br-s), 7.16 (2H, br-s).

Example 6N-(4,6-dimethyl-1-octyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

The compound (1.86 g) obtained in Example 5 was dissolved in formic acid(7.5 mL) and 8.51 M hydrogen chloride—2-propanol solution (1.98 mL) wasadded under ice-cooling. The mixture was stirred at the same temperaturefor 20 min. Diethyl ether (50 mL) was added, and the precipitatedcrystals were collected by filtration to give the title compound ascrystals (1.34 g).

IR ν (Nujol) cm⁻¹; 3290, 3225, 3059, 1676, 1508.

¹H-NMR (DMSO-d₆) δ (ppm); 0.84 (3H, br-t), 1.00-1.95 (21H, m), 2.13 (3H,s), 2.30 (3H, s), 2.95-3.50 (4H, m), 3.81 (2H, br-t), 5.50-9.00 (3H,br), 8.55 (1H, br-s), 9.37 (1H, br-s).

Example 7N-(4,6-dimethyl-1-octyl-5-ureidoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

N-(5-Amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide(500 mg) was dissolved in methylene chloride (5.0 mL), andchlorosulfonyl isocyanate (0.14 mL) was added dropwise at −60° C. Themixture was stirred at the same temperature for 3 hr and 6M hydrochloricacid (0.45 mL) was added. The mixture was stirred at room temperaturefor 30 min. Water (50 mL) was added to the reaction solution and themixture was extracted with chloroform (100 mL). The chloroform layer waswashed with saturated brine and dried over sodium sulfate. Chloroformwas evaporated under reduced pressure and the obtained crystallineresidue was recrystallized from a mixture of chloroform-diisopropylether to give the title compound as crystals (407 mg).

IR ν (Nujol) cm⁻¹; 3510, 3364, 1701, 1672, 1654, 1516.

¹H-NMR (CDCl₃) δ (ppm); 0.87 (3H, br-t), 1.00-1.60 (12H, m), 1.41 (9H,s), 2.04 (3H, s), 2.16 (3H, s), 2.90-3.40 (4H, br), 3.60-4.10 (2H, br),4.00-5.60 (3H, br), 7.10 (1H, s), 9.35 (1H, br).

Example 8N-(7-methanesulfonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide

-   (1) The compound (11.0 g) obtained in Example 1 (1) was dissolved in    acetic acid (55 mL) and fumed nitric acid (3.7 mL) was added while    timely cooling the mixture so that the reaction temperature would    not exceed 50° C. After stirring at the same temperature for 30 min,    diethyl ether (200 mL) was added, and the mixture was further    stirred under ice-cooling for 20 min. The precipitated crystals were    collected by filtration to give    1-acetyl-4,6-dimethyl-5-nitroindoline as crystals (10.7 g).

IR ν (Nujol) cm⁻¹; 1663, 1520.

¹H-NMR (CDCl₃) δ (ppm); 2.17 (3H, s), 2.24 (3H, s), 2.30 (3H, s), 3.08(2H, t, J=8.5 Hz), 4.12 (2H, t, J=8.5 Hz), 8.00 (1H, s).

-   (2) 10% Palladium-carbon (1.4 g) was suspended in methanol (300 mL)    and the compound (10.3 g) obtained (1) was added. The mixture was    subjected to catalytic hydrogenation at 40° C. and 4 kgf/cm² for 4    hr. The precipitated crystals were dissolved in chloroform and    palladium-carbon was filtered off. The filtrate was concentrated    under reduced pressure. Chloroform (50 mL) was added to the obtained    residue and the mixture was washed successively with saturated    aqueous sodium hydrogencarbonate (125 mL) and saturated brine (100    mL), and dried over sodium sulfate. Chloroform was evaporated under    reduced pressure to give 1-acetyl-5-amino-4,6-dimethylindoline as    crystals (8.74 g).

IR ν (Nujol) cm⁻¹; 1626.

¹H-NMR (CDCl₃) δ (ppm); 2.06 (3H, s), 2.16 (6H, s), 3.03 (2H, t, J=8.5Hz), 3.42 (2H, br-s), 3.97 (2H, t, J=8.5 Hz), 7.87 (1H, s).

-   (3) The compound (5.0 g) obtained in (2) was suspended in chloroform    (50 mL), and triethylamine (4.4 mL) and 2,2-dimethylundecanoyl    chloride (6.4 g) were added under ice-cooling. The mixture was    stirred at room temperature for 30 min.

Chloroform (50 mL) was added to the reaction mixture and the mixture waswashed successively with 5% aqueous citric acid (100 mL) and saturatedbrine (50 mL) and dried over sodium sulfate. Chloroform was evaporatedunder reduced pressure to giveN-(1-acetyl-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide as an oil(10.7 g). The obtained oil (10.7 g) was dissolved in acetic acid (50 mL)and fumed nitric acid (1.5 mL) was added under ice-cooling. The mixturewas stirred at room temperature for 1 hr. After the completion of thereaction, water (250 mL) was added and the mixture was stirred for 30min. The precipitated crystals were collected by filtration and thecrystals were dissolved in chloroform (100 mL). The solution was washedwith saturated aqueous sodium hydrogencarbonate (100 mL) and saturatedbrine (50 mL) and dried over sodium sulfate. Chloroform was evaporatedunder reduced pressure. Diisopropyl ether (50 mL) was added to theobtained crystalline residue and the crystals were collected byfiltration to giveN-(1-acetyl-4,6-dimethyl-7-nitroindolin-5-yl)-2,2-dimethylundecanamideas crystals (8.73 g).

IR ν (Nujol) cm⁻¹; 1659, 1532.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.93 (3H, m), 1.18-1.72 (22H, m), 2.08 (6H,s), 2.21 (3H, s), 3.04 (2H, t, J=8.0 Hz), 4.14 (2H, t, J=8.0 Hz), 7.21(1H, br-s).

-   (4) 10% Palladium-carbon (1.2 g) was suspended in methanol (250 mL)    and the compound (8.73 g) obtained in (3) was added. The mixture was    subjected to catalytic hydrogenation at 40° C., 4 kgf/cm² for 24 hr.    Palladium-carbon was filtered off, and methanol was evaporated under    reduced pressure. Chloroform (50 mL) was added to the obtained    residue, washed with saturated aqueous sodium hydrogencarbonate (50    mL) and saturated brine (50 mL) and dried over sodium sulfate.    Chloroform was evaporated under reduced pressure. Diisopropyl ether    (40 mL) was added to the obtained crystalline residue and the    crystals were collected by filtration to give    N-(1-acetyl-7-amino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide    as crystals (7.49 g).

IR ν (Nujol) cm⁻¹; 1643, 1620, 1589, 1512.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.93 (3H, m), 1.19-1.64 (22H, m), 2.00 (6H,s), 2.21 (3H, s), 2.92 (2H, t, J=8.0 Hz), 4.03 (2H, t, J=8.0 Hz),4.20-4.90 (2H, br), 6.93 (1H, br-s).

-   (5) The compound (1.0 g) obtained in (4) was dissolved in methylene    chloride (10 mL), and triethylamine (0.37 mL) and methanesulfonyl    chloride (0.2 mL) were added under ice-cooling. The mixture was    stirred at room temperature for 1 hr. Chloroform (20 mL) was added    to the reaction mixture and the mixture was washed successively with    5% aqueous citric acid (20 mL) and saturated brine (20 mL) and dried    over sodium sulfate. The solvent was evaporated under reduced    pressure to give    N-(1-acetyl-7-methanesulfonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide    as a powder (1.16 g).

IR ν (Nujol) cm⁻¹; 1651, 1645, 1634, 1155.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.93 (3H, m), 1.18-1.70 (22H, m), 2.08 (3H,s), 2.33 (6H, s), 2.79 (3H, s), 3.04 (2H, t, J=7.5 Hz), 4.15 (2H, t,J=7.5 Hz), 6.96 (1H, br-s), 8.77-8.92 (1H, br).

-   (6) The compound (1.04 g) obtained in (5) was suspended in methanol    (10 ml) and a solution of sodium hydroxide (0.42 g) in water (2.5    mL) was added at room temperature. The mixture was refluxed under    nitrogen atmosphere for 18 hr. After allowing to cool, methanol was    evaporated. Ethyl acetate (50 mL) was added, and the mixture was    washed successively with 5% aqueous citric acid (50 mL), saturated    aqueous sodium hydrogencarbonate (50 mL) and saturated brine (50 mL)    and dried over sodium sulfate. Ethyl acetate was evaporated under    reduced pressure. The obtained residue was dissolved in ethyl    acetate (10 mL) with heating and n-hexane (10 mL) was added. The    mixture was stood still in a freezer for 1 hr to allow    crystallization and the precipitated crystals were collected by    filtration to give the title compound as crystals (767 mg).

IR ν (Nujol) cm⁻¹; 1636, 1609, 1508, 1151.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.94 (3H, m), 1.17-1.64 (22H, m), 1.98 (3H,s), 2.02 (3H, s), 2.90-3.00 (5H, m), 3.45. (2H, t, J=8.0 Hz), 3.60-4.40(1H, br), 6.99 (2H, br-s).

Example 9N-(7-methanesulfonylamino-1,4,6-trimethylindolin-5-yl)-2,2-dimethylundecanamide

-   (1)    N-(1-Acetyl-7-amino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide    (5.0 g) was dissolved in chloroform (50 mL) and di-tert-butyl    dicarbonate (5.3 g) was added at room temperature. The mixture was    stirred at the same temperature for 17 hr. Chloroform was evaporated    under reduced pressure and the obtained residue was purified by    column chromatography to give    N-(1-acetyl-7-tert-butoxycarbonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide    as a powder (6.22 g).

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.93 (3H, m), 1.07-1.77 (31H, m), 2.04 (3H,s), 2.13 (3H, s), 2.30 (3H, s), 3.00 (2H, t, J=7.5 Hz), 4.11 (2H, t,J=7.5 Hz), 6.91 (1H, br-s), 8.20 (1H, br-s).

-   (2) The compound (6.22 g) obtained in (1) was dissolved in methanol    (60 mL), and a solution of sodium hydroxide (2.4 g) in water (15 mL)    was added at room temperature. The mixture was refluxed under    nitrogen atmosphere for 1.5 hr. After allowing to cool, methanol was    evaporated. Chloroform (100 mL) was added to the obtained residue,    and the mixture was washed successively with 5% aqueous citric acid    (80 mL), saturated aqueous sodium hydrogencarbonate (30 mL) and    saturated brine (30 mL) and dried over sodium sulfate. Chloroform    was evaporated under reduced pressure. n-Hexane (30 mL) was added to    the obtained crystalline residue and the crystals were collected by    filtration to give    N-(7-tert-butoxycarbonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide    as crystals (4.81 g).

IR ν (Nujol) cm⁻¹; 1672, 1639, 1543, 1514.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.94 (3H, m), 1.29-1.77 (31H, m), 1.95 (3H,s), 2.01 (3H, s), 2.50-4.60 (1H, br), 2.96 (2H, t, J=8.0 Hz), 3.58 (2H,t, J=8.0 Hz), 6.13 (1H, br-s), 6.88 (1H, br-s).

-   (3) The compound (2.03 g) obtained in (2) was dissolved in acetone    (20 mL), and potassium carbonate (1.18 g) and methyl iodide (0.4 mL)    were added at room temperature under nitrogen atmosphere. The    mixture was stirred at the same temperature for 2 hr. 5% Aqueous    citric acid (10 mL) was added and acetone was evaporated under    reduced pressure. Ethyl acetate (50 mL) was added to the obtained    residue and the mixture was washed successively with 5% aqueous    citric acid (20 mL) and saturated brine (20 mL) and dried over    sodium sulfate. Ethyl acetate was evaporated under reduced pressure    and the obtained residue was purified by column chromatography to    give    N-(7-tert-butoxycarbonylamino-1,4,6-trimethylindolin-5-yl)-2,2-dimethylundecanamide    as crystals (1.25 g).

IR ν (Nujol) cm⁻¹; 1672, 1639, 1603, 1520.

¹H-NMR (CDCl₃) δ (ppm); 0.80-0.93 (3H, m), 1.28-1.64 (31H, m), 1.96 (3H,s), 1.98 (3H, s), 2.82 (2H, t, J=8.0 Hz), 2.89 (3H, s), 3.33 (2H, t,J=8.0 Hz), 5.96 (1H, br-s), 6.82 (1H, br-s).

-   (4) The compound (1.23 g) obtained in (3) was dissolved in formic    acid (6 mL), and 8.51 M hydrogen chloride—2-propanol solution (1.5    mL) was added under nitrogen atmosphere and under ice-cooling. The    mixture was stirred at the same temperature for 15 min, neutralized    with saturated aqueous sodium hydrogencarbonate, extracted with    chloroform (50 mL), washed with saturated brine (20 mL) and dried    over sodium sulfate. Chloroform was evaporated under reduced    pressure and the obtained residue was purified by column    chromatography. n-Hexane was added to the obtained crystalline    residue and the crystals were collected by filtration to give    N-(7-amino-1,4,6-trimethylindolin-5-yl)-2,2-dimethylundecanamide as    crystals (713 mg).

IR ν (Nujol) cm⁻¹; 1641, 1522.

¹H-NMR (CDCl₃) δ (ppm); 0.80-0.93 (3H, m), 1.17-1.66 (22H, m), 2.01 (6H,s), 2.75-2.99 (4H, m), 2.79 (3H, s), 3.37 (2H, t, J=7.5 Hz), 6.80 (1H,br-s).

-   (5) The compound (703 mg) obtained in (4) was dissolved in methylene    chloride (7 mL), and methanesulfonyl chloride (0.18 mL) and    triethylamine (1.0 mL) were added under nitrogen atmosphere and    under ice-cooling. The mixture was stirred at the same temperature    for 10 min. Chloroform (30 mL) was added to the reaction mixture,    and the mixture was washed successively with 5% aqueous citric acid    (30 mL) twice and saturated brine (20 mL) and dried over sodium    sulfate. The solvent was evaporated under reduced pressure and the    obtained residue was purified by column chromatography to give the    title compound as crystals (510 mg).

IR ν (Nujol) cm⁻¹; 1641, 1528, 1148.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.94 (3H, m), 1.20-1.72 (22H, m), 2.01 (3H,s), 2.13 (3H, s), 2.82-3.03 (2H, m), 2.97 (3H, s), 3.02 (3H, s), 3.43(2H, t, J=7.5 Hz), 6.13 (1H, br-s), 6.80 (1H, 20 br-s).

Example 10N-(5-methanesulfonylaminomethyl-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

-   (1) The compound (10.0 g) obtained in Example 1 (4) was dissolved in    concentrated hydrochloric acid (50 mL), and 35% formalin (4.2 g) and    zinc chloride (900 mg) were added. The mixture was stirred while    introducing a hydrogen chloride gas at 50° C. for 2 hr. The reaction    solution was poured into ice water (200 mL) and the mixture was    extracted twice with chloroform (150 mL). The chloroform layers were    combined, washed with saturated brine (150 mL) and dried over sodium    sulfate. Chloroform was evaporated under reduced pressure and the    obtained    N-(1-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    (10.0 g) was suspended in N,N-dimethylformamide (50 mL). Potassium    phthalimide (6.7 g) was added, and the mixture was stirred at room    temperature for 20 hr. Ethyl acetate (700 mL) was added, and the    mixture was washed with water (500 mL) and saturated brine (300 mL),    dried over sodium sulfate and concentrated under reduced pressure.    The precipitated crystals were collected by filtration to give    N-(1-acetyl-4,6-dimethyl-5-phthalimidomethylindolin-7-yl)-2,2-dimethylpropanamide    (12.4 g).

IR ν (Nujol) cm⁻¹; 1770, 1708, 1674, 1647.

¹H-NMR (CDCl₃) δ (ppm); 1.25 (9H, s), 2.23 (3H, s), 2.28 (3H, s), 2.36(3H, s), 2.80-3.30 (2H, br), 3.90-4.30 (2H, br), 4.98 (2H, s), 7.50-7.90(4H, m), 9.13 (1H, br-s).

-   (2) The compound (12.0 g) obtained (1) was dissolved in a mixture of    methanol (100 mL) and chloroform (50 mL) and hydrazine monohydrate    (2.1 g) was added. The mixture was refluxed for 3 hr. The solvent    was evaporated under reduced pressure and the obtained residue was    dissolved in chloroform (200 mL). The mixture was washed    successively with saturated aqueous sodium hydrogencarbonate (100    mL), saturated brine (100 mL) and dried over sodium sulfate.    Chloroform was evaporated under reduced pressure and the obtained    N-(1-acetyl-5-aminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    was dissolved in chloroform (100 mL). Di-tert-butyl dicarbonate    (6.0 g) was added, and the mixture was stirred at room temperature    for 1 hr, washed with saturated brine (100 mL) and dried over sodium    sulfate. Chloroform was evaporated under reduced pressure and the    obtained residue was purified by column chromatography to give    N-(1-acetyl-5-tert-butoxycarbonylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (11.5 g).

IR ν (Nujol) cm⁻¹; 1678, 1645, 1514.

¹H-NMR (CDCl₃) δ (ppm); 1.27 (9H, s), 1.44 (9H, s), 2.19 (3H, s), 2.24(3H, s), 2.30 (3H, s), 2.80-3.30 (2H, br), 3.90-4.30 (2H, br), 4.36 (2H,s), 4.40 (1H, br), 9.12 (1H, br-s).

-   (3) The compound (11.5 g) obtained in (2) was dissolved in methanol    (200 mL) and 2.42 M aqueous sodium hydroxide solution (60 mL) was    added. The mixture was stirred at 50° C. for 15 hr. Methanol was    evaporated under reduced pressure and the residue was dissolved in    chloroform (200 mL). The mixture was washed successively with water    (100 mL) and saturated brine (100 mL) and dried over sodium sulfate.    Chloroform was evaporated under; reduced pressure and the obtained    N-(5-tert-butoxycarbonylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    was dissolved in N,N-dimethylformamide (50 mL). Octyl iodide    (11.4 g) and potassium carbonate (6.6 g) were added and the mixture    was stirred at 40° C. for 15 hr. Ethyl acetate (300 mL) was added,    and the mixture was washed successively with water (100 mL) and    saturated brine (100 mL) and dried over sodium sulfate. Ethyl    acetate was evaporated under reduced pressure and the obtained    residue was purified by column chromatography to give    N-(5-tert-butoxycarbonylaminomethyl-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (7.9 g).

IR ν (Nujol) cm⁻¹; 1695, 1674, 1649, 1541.

¹H-NMR (CDCl₃) 5 (ppm); 0.88 (3H, br-t), 1.10-1.90 (12H, m), 1.34 (9H,s), 1.44 (9H, s), 2.08 (3H, s), 2.16 (3H, s), 2.83 (2H, t, J=8.5 Hz),3.13 (2H, t, J=7.1 Hz), 3.42 (2H, t, J=8.5 Hz), 4.26 (2H, s), 4.30 (1H,br-s), 6.80 (1H, br-s).

-   (4) The compound (4.0 g) obtained in (3) was dissolved in chloroform    (100 mL), and 8M hydrogen chloride—2-propanol solution (11 mL) was    added under ice-cooling. The mixture was stirred at room temperature    for 1 hr, washed successively with saturated aqueous sodium    hydrogencarbonate (70 mL) and saturated brine (70 mL) and dried over    sodium sulfate. Methanesulfonyl chloride (939 mg) and triethylamine    (830 mg) were added to the obtained solution under ice-cooling and    the mixture was stirred at the same temperature for 30 min, washed    successively with 5% aqueous citric acid (70 mL) and saturated brine    (70 mL) and dried over sodium sulfate. Chloroform was evaporated    under reduced pressure. The obtained residue was purified by column    chromatography and the obtained oil (1.5 g) was dissolved in    chloroform (30 mL). 8M hydrogen chloride—2-propanol solution (0.48    mL) was added under ice-cooling. chloroform was evaporated under    reduced pressure to give the title compound as a powder (1.2 g).

IR ν (Nujol) cm⁻¹; 1666.

¹H-NMR (CDCl₃) δ (ppm); 0.79 (3H, br-t), 1.10-1.90 (12H, m), 1.34 (9H,s), 2.18 (3H, s), 2.29 (3H, s), 2.60-3.20 (4H, m), 2.89 (3H, s),3.40-4.20 (3H, br), 4.29 (2H, s), 4.98 (1H, br-s), 9.34 (1H, br-s).

According to Examples 1 to 10, the compounds of Examples 11 to 45 weresynthesized.

Example 11N-(5-methanesulfonylamino-4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3203, 1666, 1510.

¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, br-t), 1.10-1.80 (6H, m), 1.33 (9H,s), 2.10 (3H, s), 2.15 (3H, s), 2.83 (2H, t, J=8.4 Hz), 2.97 (3H, s),3.18 (2H, t, J=8.0 Hz), 3.45 (2H, t, J=8.4 Hz), 6.04 (1H, br-s), 6.83(1H, br-s).

Example 12N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3124, 1652, 1506.

¹H-NMR (CDCl₃) δ (ppm); 0.93 (3H, br-t), 1.10-1.70 (4H, m), 1.33 (9H,s), 2.10 (3H, s), 2.14 (3H, s), 2.83 (2H, t, J=8.4 Hz), 2.97 (3H, s),3.18 (2H, t, J=8.0 Hz), 3.45 (2H, t, J=8.4 Hz), 6.09 (1H, br-s), 6.84(1H, br-s).

Example 13N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methylbutyl)indolin-7-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3205, 1666, 1504.

¹H-NMR (CDCl₃) δ (ppm); 0.92 (6H, d, J=6.0 Hz), 1.20-1.60 (3H, m), 1.34(9H, s), 2.09 (3H, s), 2.14 (3H, s), 2.81 (2H, t, J=8.3 Hz), 2.96 (3H,s), 3.19 (2H, br-t), 3.43 (2H, t, J=8.3 Hz), 6.15 (1H, br-s), 6.86 (1H,br-s).

Example 14N-(5-methanesulfonylamino-4,6-dimethyl-1-propylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3205, 1662, 1506.

¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, t, J=7.2 Hz), 1.30-1.80 (2H, m), 1.34(9H, s), 2.07 (3H, s), 2.10 (3H, s), 2.81 (2H, t, J=8.4 Hz), 2.95 (3H,s), 3.14 (2H, t, J=7.2 Hz), 3.44 (2H, t, J=8.4 Hz), 6.23 (1H, br-s),6.88 (1H, br-s).

Example 15N-[5-methanesulfonylamino-4,6-dimethyl-1-(2-methylpropyl)indolin-7-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3269, 1658, 1596.

¹H-NMR (CDCl₃) δ (ppm); 0.93 (6H, d, J=6.4 Hz), 1.20-1.60 (1H, m), 1.34(9H, s), 2.06 (3H, s), 2.09 (3H, s), 2.82 (2H, t, J=8.4 Hz), 2.96 (3H,s), 3.01 (2H, d, J=6.4 Hz), 3.41 (2H, t, J=8.4 Hz), 6.27 (1H, br-s),6.81 (1H, br-s).

Example 16N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3197, 1664, 1506.

¹H-NMR (CDCl₃) δ (ppm); 0.94 (3H, t, J=7.0 Hz), 1.21 (9H, s), 1.99 (3H,s), 2.11 (3H, s), 2.77 (2H, br-t), 2.88 (3H, s), 3.19 (2H, br-t), 3.37(2H, br-t), 8.52 (1H, br-s), 8.67 (1H, br-s).

Example 17N-(4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3448, 3336, 3240, .3163, 2501, 1674, 1340, 1180,1163.

¹H-NMR (DMSO-d₆) δ (ppm); 0.86 (3H, t, J=7.4 Hz), 1.30 (9H, s),1.50-2.00 (2H, m), 2.14 (3H, s), 2.30 (3H, s), 2.90-3.40 (4H, m),3.60-4.00 (2H, br-t), 5.00-8.00 (3H, br), 8.53 (1H, br-s), 9.32 (1H,br-s).

Example 18N-(4,6-dimethyl-1-pentyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3589, 3471, 3340, 3230, 3138, 2528, 1672, 1340, 1186,1164.

¹H-NMR (DMSO-d₆) δ (ppm); 0.85 (3H, t, J=5.7 Hz), 1.00-2.00 (6H, m),1.30 (9H, s), 2.14 (3H, s), 2.30 (3H, s), 2.90-3.40 (4H, m), 3.60-4.00(2H, br-t), 5.00-8.00 (3H, br), 8.54 (1H, br-s), 9.32 (1H, br-s).

Example 19N-(1-butyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3456, 3340, 3244, 3136, 2732, 2522, 1674, 1627, 1377,1338, 1180, 1163.

¹H-NMR (DMSO-d₆) δ (ppm); 0.87 (3H, br-t), 0.90-2.00 (4H, m), 1.30 (9H,s), 2.14 (3H, s), 2.30 (3H, s), 2.90-3.40 (4H, m), 3.60-4.00 (2H, br-t),4.20-8.20 (3H, br), 8.55 (1H, br-s), 9.33 (1H, br-s).

Example 20N-[1-(3-methylbutyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride.

IR ν (Nujol) cm⁻¹; 3233, 3105, 2472, 2362, 1672, 1629, 1165.

¹H-NMR (DMSO-d₆) 5 (ppm); 0.85 (6H, d, J=5.0 Hz), 1.30 (9H, s),1.30-1.80 (3H, m), 2.14 (3H, s), 2.30 (3H, s), 2.90-3.40 (4H, m),3.60-4.00 (2H, br), 5.00-8.50 (3H, br), 8.54 (1H, br-s), 9.30 (1H,br-s).

Example 21N-[1-(2-methylpropyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3608, 3446, 3342, 3249, 3141, 2729, 2567, 2526, 1668,1627, 1377, 1338, 1180, 1163.

¹H-NMR (DMSO-d₆) δ (ppm); 0.98 (6H, d, J=5.0 Hz), 1.29 (9H, s) 1.80-2.50(1H, m), 2.12 (3H, s), 2.29 (3H, s), 2.80-3.40 (4H, m), 3.60-3.90 (2H,br), 5.00-8.00 (3H, br), 8.48 (1H, br-s), 9.27 (1H, br-s).

Example 22N-(1-hexyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3360, 1665.

¹H-NMR (CDCl₃) δ (ppm); 0.88 (3H, br-t), 1.16-1.69 (8H, m), 1.33 (9H,s), 2.10 (3H, s), 2.14 (3H, s), 2.73-3.55 (6H, m), 2.97 (3H, s), 6.09(1H, br-s), 6.83 (1H, br-s).

Example 23N-[4,6-dimethyl-7-(2-propanesulfonylamino)indolin-5-yl]-2,2-dimethylundecanamidehydrochloride

IR ν (Nujol) cm⁻¹; 1647, 1142.

¹H-NMR (DMSO-d₆) δ (ppm); 0.80-0.95 (3H, m), 1.00-1.80 (28H, m), 2.03(3H, s), 2.14 (3H, s), 3.00-3.80 (5H, m), 3.50-7.50 (2H, br), 8.95 (1H,br-s), 9.29 (1H, br-s).

Example 24N-[4,6-dimethyl-7-(2-propanesulfonylamino)indolin-5-yl]-2,2-dimethyloctanamide.

IR ν (Nujol) cm⁻¹; 1643, 1620.

¹H-NMR (CDCl₃) δ (ppm); 0.80-0.95 (3H, m), 1.00-1.80 (16H, m) 1.40 (6H,d, J=7.0 Hz), 1.97 (3H, s), 2.00 (3H, s), 2.60-3.80 (6H, m), 6.70-7.10(1H, br), 6.98 (1H, br-s).

Example 25N-[4,6-dimethyl-7-(p-toluene)sulfonylaminoindolin-5-yl]-2,2-dimethylundecanamide

IR ν (Nujol) cm⁻¹; 1639, 1165.

¹H-NMR (CDCl₃) δ (ppm); 0.81-0.94 (3H, m), 1.20-1.80 (22H, m), 1.46 (3H,s), 1.94 (3H, s), 2.38 (3H, s), 2.60-4.20 (2H, br), 2.88 (2H, t, J=8.0Hz), 3.34 (2H, t, J=8.0 Hz), 6.86 (1H, br-s), 7.21 (2H, d, J=8.0 Hz),7.64 (2H, d, J=8.0 Hz).

Example 26N-(4,6-dimethyl-7-sulfamoylaminoindolin-5-yl)-2,2-dimethylundecanamidehydrochloride

IR ν (Nujol) cm⁻¹; 1645, 1159.

¹H-NMR (DMSO-d6) δ (ppm); 0.80-0.95 (3H, m), 1.10-1.80 (22H, m), 2.03(3H, s), 2.15 (3H, s), 3.00-3.20 (2H, m), 3.20-7.80 (4H, br), 3.60-3.80(2H, m), 8.80-9.00 (2H, br-s).

Example 27N-(4,6-dimethyl-7-ureidoindolin-5-yl)-2,2-dimethylundecanamide

IR ν (Nujol) cm⁻¹; 1670, 1638.

¹H-NMR (CDCl₃) δ (ppm); 0.80-0.95 (3H, m), 1.10-1.80 (22H, m), 1.72 (3H,s), 1.88 (3H, s), 2.80-3.80 (5H, m), 5.06 (2H, br-s), 6.70-6.90 (1H,br), 7.35 (1H, br-s).

Example 28 N-[4,6-dimethyl-7-(2-propanesulfonylamino)indolin-5-yl]-cyclohexanecarboxamide

IR ν (Nujol) cm⁻¹; 3330, 3204, 1649, 1512, 1377, 1145, 1136.

¹H-NMR (CDCl₃) δ (ppm); 1.20-2.50 (11H, m), 1.40 (6H, d, J=6.8 Hz), 1.96(6H, s), 2.91 (2H, t, J=8.2 Hz), 3.25 (1H, septet, J=6.8 Hz), 3.49 (2H,t, J=8.2 Hz), 4.74 (1H, br), 6.64 (1H, br), 7.26 (1H, br).

Example 29N-[4,6-dimethyl-7-(1-octanesulfonylamino)indolin-5-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3327, 3165, 1632, 1607, 1510.

¹H-NMR (CDCl₃) δ (ppm); 0.87 (3H, br-t), 1.10-1.60 (12H, m), 1.36 (9H,s), 1.96 (3H, s), 2.03 (3H, s), 2.70-3.20 (4H, m), 3.43 (2H, t, J=8.1Hz), 4.80 (1H, br), 6.83 (1H, br), 7.00 (1H, br).

Example 30N-[4,6-dimethyl-7-(2-propanesulfonylamino)indolin-5-yl]-benzamide

IR ν (Nujol) cm⁻¹; 1645, 1528, 1138.

¹H-NMR (DMSO-d₆) δ (ppm); 1.31 (6H, d, J=6.5 Hz), 1.98 (3H, s), 2.10(3H, s), 2.80-3.70 (5H, m), 4.80-5.20 (1H, br), 7.40-7.70 (3H, m),7.80-8.10 (2H, m), 8.42 (1H, br-s), 9.53 (1H, br-s).

Example 31N-(5-methanesulfonylamino-1,4,6-trimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3193, 1662, 1506.

¹H-NMR (DMSO-d₆) δ (ppm); 1.20 (9H, s), 1.98 (3H, s), 2.12 (3H, s),2.60-3.00 (2H, m), 2.80 (3H, s), 2.87 (3H, s), 3,26 (2H, br-t), 8.53(1H, s), 8.67 (1H, s).

Example 32N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3184, 3099, 1690, 1510, 1329, 1180, 1155.

¹H-NMR (CDCl₃) δ (ppm); 0.96 (3H, br-t), 1.10-2.30 (5H, m), 1.44 (9H,s), 2.18 (3H, s), 2.21 (3H, s), 2.90-3.40 (4H, m), 3.02 (3H, s),3.50-4.20 (2H, m), 7.34 (1H, br-s), 9.59 (1H, br-s).

Example 33N-[5-methanesulfonylamino-4,6-dimethyl-1-(2-methylpropyl)indolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3236, 3032, 1692, 1506, 1321, 1175, 1155.

¹H-NMR (CDCl₃) δ (ppm); 0.95-1.35 (6H, m), 1.43 (9H, s), 1.60-2.00 (1H,br), 2.10-2.55 (1H, m), 2.16 (3H, s), 2.19 (3H, s), 2.85-3.40 (4H, m),3.01 (3H, s), 3.60-4.30 (2H, m), 7.50 (1H, br-s), 9.66 (1H, br-s).

Example 34N-(5-methanesulfonylamino-4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3211, 3148, 1670, 1508, 1325, 1157.

¹H-NMR (CDCl₃) δ (ppm); 0.91 (3H, br-t), 1.20-2.40 (7H, m), 1.44 (9H,s), 2.18 (3H, s), 2.21 (3H, s), 2.90-3.40 (4H, m), 3.02 (3H, s),3.60-4.20 (2H, m), 7.36 (1H, br-s), 9.58 (1H, br-s).

Example 35N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methylbutyl)indolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3219, 3080, 1686, 1666, 1506, 1325, 1157.

¹H-NMR (CDCl₃) δ (ppm); 0.94 (6H, d, J=5.7 Hz), 1.20-2.40 (4H, m), 1.43(9H, s), 2.18 (3H, s), 2.26 (3H, s), 2.90-3.40 (4H, m), 3.03 (3H, s),3.60-4.20 (2H, m), 7.12 (1H, br-s), 9.52 (1H, br-s).

Example 36N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylbutanamide

IR ν (Nujol) cm⁻¹; 3360, 3202, 1661, 1504, 1377, 1321, 1151.

¹H-NMR (CDCl₃) δ (ppm); 0.70-1.10 (6H, m), 1.10-1.90 (6H, m), 1.29 (6H,s), 2.11 (3H, s), 2.13 (3H, s), 2.84 (2H, t, J=8.4 Hz), 2.96 (3H, s),3.18 (2H, t, J=6.8 Hz), 3.44 (2H, t, J=8.4 Hz), 6.16 (1H, br-s), 6.85(1H, br-s).

Example 37N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2-methylpropanamide

IR ν (Nujol) cm⁻¹; 3263, 1657, 1520, 1377, 1310, 1155, 1144.

¹H-NMR (DMSO-d₆) δ (ppm); 0.77-1.90 (7H, m), 1.10 (6H, d, J=6.6 Hz),1.90-2.35 (1H, m), 2.00 (3H, s), 2.11 (3H, s), 2.40-3.60 (6H, m), 2.89(3H, s), 8.51 (1H, br-s), 8.93 (1H, br-s).

Example 38N-(1-isopropyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3176, 1656.

¹H-NMR (CDCl₃) δ (ppm); 1.03 (6H, d, J=6.6 Hz), 1.21 (9H, s), 2.00 (3H,s), 2.12 (3H, s), 2.76 (2H, br-t), 2.89 (3H, s), 3.37 (2H, br-t),4.00-4.20 (1H, m), 8.53 (1H, br-s), 8.70 (1H, br-s).

Example 39N-[1-(2,2-dimethylpropyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3348, 2467, 2361, 1668, 1319, 1184, 1150.

¹H-NMR (CDCl₃) δ (ppm); 1.21 (9H, s), 1.48 (9H, s), 1.50-1.70 (1H, br),2.16 (3H, s), 2.26 (3H, s), 3.03 (5H, br-s), 3.10-3.40 (2H, m),3.80-4.30 (2H, m), 7.27 (1H, br-s), 9.50-7.70 (1H, br).

Example 40N-(1-cyclobutylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3205, 1662.

¹H-NMR (DMSO-d₆) δ (ppm); 1.21 (9H, s), 1.50-2.10 (7H, m), 1.99 (3H, s),2.11 (3H, s), 2.75 (2H, br-t), 2.88 (3H, s), 3.10-3.60 (4H, m), 8.52(1H, br-s), 8.63 (1H, br-s).

Example 41N-(1-cyclopentyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3219, 1647.

¹H-NMR (DMSO-d6) δ (ppm); 1.21 (9H, s), 1.30-1.80 (8H, m), 1.98 (3H, s),2.10 (3H, s), 2.70 (2H, br-t), 2.77 (3H, s), 3.37 (2H, br-t), 4.20-4.60(1H, m), 8.51 (1H, br-s), 8.68 (1H, br-s).

Example 42N-(1-cyclopropylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3258, 1655.

¹H-NMR (DMSO-d₆) δ (ppm); 0.10-1.10 (5H, m), 1.21 (9H, s), 1.99 (3H, s),2.10 (3H, s), 2.78 (2H, t, J=8.1 Hz), 2.78 (3H, s), 3.48 (2H, d, J=6.5Hz), 3.07 (2H, t, J=8.1 Hz), 8.52 (1H, br-s), 8.68 (1H, br-s).

Example 43N-(1-cyclopentyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3200, 2480, 1705, 1665, 1502, 1335, 1151.

¹H-NMR (DMSO-d₆) δ (ppm); 1.28 (9H, s), 1.37-1.85 (8H, m), 2.13 (3H, s),2.27 (3H, s), 3.00-4.00 (3H, br), 3.11 (2H, br-t), 3.78 (2H, br-t),6.70-7.00 (1H, br), 8.50 (1H, br-s), 9.23 (1H, br-s).

Example 44N-[5-(N-acetylsulfamoylamino)-4,6-dimethyl-1-propylindolin-7-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3350, 3080, 1699, .1639, 1514, 1344, 1231, 1159.

¹H-NMR (DMSO-d₆) δ (ppm); 0.82 (3H, t, J=7.1 Hz), 1.21 (9H, s), 1.92(6H, s), 1.46 (2H, sextet, J=8.1 Hz), 2.04 (3H, s), 2.77 (2H, t, J=8.3Hz), 3.08 (2H, t, J=8.3 Hz), 3.28-3.39 (2H, m), 8.67 (1H, br-s), 9.26(1H, br-s), 11.29 (1H, br-s).

Example 45N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methyl-2-butenyl)indolin-7-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3130, 1641, 1600.

¹H-NMR (DMSO-d₆) δ (ppm); 1.19 (9H, s), 1.61 (3H, s), 1.65 (3H, s), 2.00(3H, s), 2.10 (3H, s), 2.74 (2H, br-t), 2.89 (3H, s), 3.34 (2H, br-t),3.78 (2H, d, J=6.3 Hz), 5.00-5.30 (1H, m), 8.53 (1H, br-s), 8.69 (1H,br-s).

Example 46N-[1-(2-ethoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

-   (1) N-(4,6-Dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    (800 mg) was dissolved in N,N-dimethylformamide (8.0 mL) and    diisopropylethylamine (0.93 mL) and bromomethyl ethyl ether (0.62    mL) were added under a nitrogen atmosphere. The mixture was stirred    at 100° C. for 16 hr. Ethyl acetate (100 mL) was added to the    reaction mixture and the mixture was washed successively with 5%    aqueous citric acid, water and saturated brine (each 50 mL) and    dried over sodium sulfate. The obtained residue was purified by    silica gel column chromatography to give    N-[1-(2-ethoxyethyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    as crystals (820 mg).

IR ν (Nujol) cm⁻¹; 3279, 1651, 1593, 1512.

¹H-NMR (CDCl₃) δ (ppm); 1.16 (3H, t, J=6.8 Hz), 1.31 (9H, s), 2.01 (3H,s), 2.10 (3H, s), 2.70-3.00 (2H, m), 3.40-3.70 (8H, m), 7.97 (1H, br-s).

-   (2) The compound (800 mg) obtained in (1) was dissolved in methanol    (16 mL), and 5% palladium-carbon (200 mg) was added. The mixture was    subjected to catalytic hydrogenation at 35° C., 3 kgf/cm² for 11 hr.    Palladium-carbon was filtered off, and the solvent was evaporated    under reduced pressure. Diethyl ether (20 mL) was added to the    obtained crystalline residue, and the crystals were washed by    stirring the mixture and collected by filtration to give    N-[5-amino-i-(2-ethoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide    as crystals (570 mg).

IR ν (Nujol) cm⁻¹; 3273, 1651, 1504, 1481.

¹H-NMR (CDCl₃) δ (ppm); 1.16 (3H, t, J=7.0 Hz), 1.34 (9H, s), 1.90 (3H,s), 2.03 (3H, s), 2.70-3.00 (2H, m), 3.00-3.70 (10H, m), 7.45 (1H,br-s).

-   (3) tert-Butanol (0.23 mL) was dissolved in methylene chloride (4    mL) and chlorosulfonyl isocyanate (0.21 mL) was added dropwise at    −10° C. The mixture was stirred at the same temperature for 20 min.    The compound (400 mg) obtained in (2) and triethylamine (0.33 mL)    were added, and the mixture was stirred at the same temperature for    15 min. Ethyl acetate (50 mL) was added to the reaction mixture and    the mixture was washed successively with 5% aqueous citric acid, 5%    aqueous sodium hydrogencarbonate and saturated brine (each 50 mL)    and dried over sodium sulfate. The solvent was evaporated under    reduced pressure and the obtained residue was purified by silica gel    column chromatography to give    N-[5-(N-tert-butoxycarbonyl)sulfamoylamino-1-(2-ethoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide    (440 mg).

IR ν (Nujol) cm⁻¹; 3263, 3103, 1728, 1660, 1597.

¹H-NMR (CDCl₃) δ (ppm); 1.13 (3H, t, J=7.0 Hz), 1.31 (9H, s), 1.49 (9H,s), 2.03 (3H, s), 2.15 (3H, s), 2.70-3.00 (2H, m), 3.30-3.70 (8H, m),6.47 (1H, br-s), 6.50-8.40 (1H, br), 7.80 (1H, br-s).

-   (4) The title compound was obtained as crystals (235 mg) by treating    in the same manner as in Example 6 using the compound (420 mg)    obtained in (3)

IR ν (Nujol) cm⁻¹; 3543, 3226, 3115, 1676, 1657, 1630, 1504.

¹H-NMR (DMSO-d₆) δ (ppm); 1.12 (3H, t, J=7.1 Hz), 1.26 (9H, s), 2.11(3H, s), 2.26 (3H, s), 3.05-3.15 (2H, m), 3.30-3.40 (2H, m), 3.44 (2H,q, J=7.1 Hz), 3.50-5.00 (1H, br), 3.66 (2H, br-t), 3.78 (2H, br-t),6.50-7.50 (2H, br), 8.46 (1H, br-s), 9.15 (1H, br-s).

Example 47N-[1-(2-methoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3363, 3136, 1680, 1628, 1504, 1339, 1178, 1161, 1126.

¹H-NMR (DMSO-d₆) δ (ppm); 1.25 (9H, s), 2.10 (3H, s), 2.24 (3H, s),2.96-3.11 (2H, m), 3.27 (3H, s), 3.20-4.40 (8H, m), 6.50-7.10 (1H, br),8.30-8.50 (1H, br), 8.90-9.10 (1H, m).

Example 48N-[1-(2-ethoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3350, 3200, 1663, 1506, 1317, 1190, 1151, 1123, 1109.

¹H-NMR (CDCl₃) δ (ppm); 1.16 (3H, t, J=7.1 Hz), 1.32 (9H, s), 2.10 (3H,s), 2.19 (3H, s), 2.88 (2H, t, J=8.6 Hz), 2.98 (3H, s), 3.49 (2H, q,J=7.1 Hz), 3.50 (2H, t, J=8.6 Hz), 3.47-3.60 (4H, m), 5.70-5.90 (1H, m),7.87 (1H, br-s).

Example 49N-[1-(2-methoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3360, 3200, 1662, 1600, 1505, 1318, 1190, 1151, 1114.

¹H-NMR (CDCl₃) δ (ppm); 1.31 (9H, s), 2.09 (3H, s), 2.17 (3H, s), 2.88(2H, t, J=8.8 Hz), 2.98 (3H, s), 3.36 (3H, s), 3.43-3.62 (6H, m),5.78-6.00 (1H, m), 7.73 (1H, br-s).

Example 50N-(2-methoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

-   (1) 2-Hydroxymethyl-4,6-dimethylindole (14.5 g) was dissolved in    acetic acid (145 mL) and sodium cyanoborohydride (11.6 g) was added    in portions at 10° C. The mixture was stirred at the same    temperature for 1 hr. A solution of sodium hydroxide (101 g) in    water (400 mL) was added dropwise, and the mixture was extracted    with ethyl acetate (1 L), washed successively with water and    saturated brine (each 500 mL) and dried over sodium sulfate. Ethyl    acetate was evaporated under reduced pressure to give    2-hydroxymethyl-4,6-dimethylindoline as an oil (13.8 g). The    obtained oil was dissolved in chloroform (138 mL), and acetic    anhydride (22 mL) and triethylamine (32.6 mL) were added under    ice-cooling. The mixture was stirred at room temperature for 2,    days. The reaction mixture was washed successively with 5% aqueous    citric acid, water and saturated brine (each 200 mL) and dried over    sodium sulfate. Chloroform was evaporated under reduced pressure to    give 2-acetoxymethyl-1-acetyl-4,6-dimethylindoline as an oil (18.3    g). The obtained oil was dissolved in methanol (200 mL) and 1M    aqueous solution of lithium hydroxide (93 mL) was added under    ice-cooling. The mixture was stirred at the same temperature for 30    min. The reaction mixture was adjusted to pH 4 with 2M hydrochloric    acid and methanol was evaporated under reduced pressure. Diethyl    ether (100 mL) was added to the obtained residue and, after stirring    under ice-cooling for 30 min, the precipitated crystals were    collected by filtration to give    1-acetyl-2-hydroxymethyl-4,6-dimethylindoline (12.18 g).

IR ν (Nujol) cm⁻¹; 3327, 1626, 1589.

¹H-NMR (CDCl₃) δ (ppm); 1.50-2.20 (1H, br), 2.19 (3H, s), 2.31 (3H, s),2.40 (3H, s), 2.30-2.80 (1H, m), 3.00-3.40 (1H, m), 3.65 (2H, d, J=6.4Hz), 4.50-5.20 (1H, br), 6.20-8.00 (1H, br), 6.70 (1H, s).

-   (2) The compound (8.34 g) obtained in (1) was dissolved in    N,N-dimethylformamide (83 mL), and sodium hydride (60% oil    suspension) (1.39 g) was added in portions under a nitrogen    atmosphere and under ice-cooling. The mixture was stirred at room    temperature for 10 min and methyl iodide (11.8 mL) was added. The    mixture was stirred at 80° C. for 2 hr. Ethyl acetate (500 mL) was    added, and the mixture was washed successively with 5% aqueous    citric acid, water and saturated brine (each 500 mL) and dried over    sodium sulfate. Ethyl acetate was evaporated under reduced pressure    and the obtained residue was purified by silica gel column    chromatography to give 1-acetyl-2-methoxymethyl-4,6-dimethylindoline    as crystals. (3.95 g).

IR ν (Nujol) cm⁻¹; 1660, 1597.

¹H-NMR (CDCl₃) δ (ppm); 2.20 (3H, s), 2.31 (6H, s), 2.70-2.90 (1H, m),3.00-3.20 (1H, m), 3.25-3.35 (1H, m), 3.34 (3H, s), 3.40-3.65 (1H, m),4.54, 4.98 (1H, br-s, br-s), 6.69 (1H, s), 6.60-6.90, 7.70-7.90 (1H, br,br).

-   (3) The compound (4.17 g) obtained in (2) was dissolved in    chloroform (60 mL), and bromine (1.0 mL) was added dropwise under    ice-cooling. The mixture was stirred at the same temperature for 20    min. The reaction solution was washed successively with 5% aqueous    sodium hydrogensulfite, 5% aqueous sodium hydrogencarbonate and    saturated brine (each 50 mL) and dried over sodium sulfate.    Chloroform was evaporated under reduced pressure to give    1-acetyl-5-bromo-2-methoxymethyl-4,6-dimethylindoline (5.21 g).

IR ν (Nujol) cm⁻¹; 1662, 1585.

¹H-NMR (CDCl₃) 5 (ppm); 2.31 (6H, s), 2.40 (3H, s), 2.70-3.00 (1H, m),3.10-3.25 (1H, m), 3.25-3.35 (1H, m), 3.34 (3H, s), 3.35-3.50 (1H, m),4.50-4.60, 4.80-5.10 (1H, br, br), 6.70-7.00, 7.80-8.00 (1H, br, br).

-   (4) The compound (5.21 g) obtained in (3) was dissolved in acetic    acid (52 mL), and concentrated sulfuric acid (1.78 mL) and fumed    nitric acid (1.12 mL) were added at 15° C. The mixture was stirred    at the same temperature for 20 min. The reaction solution was poured    into ice water (300 mL) and the precipitated crystals were collected    by filtration. The obtained crystals were dissolved in chloroform    (100 mL) and the solution was washed successively with 5% aqueous    sodium hydrogencarbonate and saturated brine and dried over sodium    sulfate. Chloroform was evaporated under reduced pressure to give    1-acetyl-5-bromo-2-methoxymethyl-4,6-dimethyl-7-nitroindoline as    crystals (5.9 g).

IR ν (Nujol) cm⁻¹; 1672, 1537.

¹H-NMR (CDCl₃) δ (ppm); 2.29 (3H, s), 2.37 (3H, s), 2.49 (3H, s), 2.82(1H, d, J=16.1 Hz), 3.30 (1H, dd, J=16.1, 8.6 Hz), 3.35-3.45 (1H, m),3.39 (3H, s), 3.49 (1H, dd, J=9.8, 6.8 Hz), 4.55-4.65 (1H, m).

-   (5) The compound (5.9 g) obtained in (4) was dissolved in methanol    (185 mL), and 5% palladium-carbon (1.78 g) was added. The mixture    was subjected to catalytic hydrogenation at 35° C., 3 kgf/cm² for 16    hr. Palladium-carbon was filtered off, and the solvent was    evaporated under reduced pressure. Ethyl acetate (50 mL) was added    to the obtained crystalline residue and the crystals were washed by    stirring the mixture and collected by filtration to give    1-acetyl-2-methoxymethyl-4,6-dimethylindoline hydrobromide as    crystals (4.95 g). The obtained crystals were dissolved in methylene    chloride (50 mL), and pivaloyl chloride (1.94 mL) was added and    triethylamine (4.4 mL) was added dropwise under ice-cooling. The    mixture was stirred at the same temperature for 1 hr, and the    reaction mixture was washed successively with 5% aqueous citric    acid, water and saturated brine (each 50 mL) and dried over sodium    sulfate. Methylene chloride was evaporated under reduced pressure    and the obtained residue was purified by silica gel column    chromatography to give    N-(1-acetyl-2-methoxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    (4.87 g).

IR ν (Nujol) cm⁻¹; 3253, 1739, 1676, 1647, 1589.

¹H-NMR (CDCl₃) δ (ppm); 1.26 (9H, s), 2.17 (3H, s), 2.19 (3H, s), 2.38(3H, s), 2.54 (1H, d, J=15.6 Hz), 3.18 (1H, dd, J=15.6, 8.0 Hz), 3.29(3H, s), 3.30-3.37 (2H, m), 4.55-4.65 (1H, m), 6.88 (1H, s), 8.93 (1H,s).

-   (6) The compound (1.5 g) obtained in (5) was dissolved in acetic    acid (7.5 mL), and concentrated sulfuric acid (0.48 mL) and fumed    nitric acid (0.28 mL) were added at 15° C. The mixture was stirred    at the same temperature for 20 min. The reaction solution was poured    into ice water (150 mL) and the precipitated crystals were collected    by filtration. The obtained crystals were dissolved in-chloroform    (50 mL), washed successively with 5% aqueous sodium    hydrogencarbonate and saturated brine (each 50 mL) and dried over    sodium sulfate. Chloroform was evaporated under reduced pressure to    give    N-(1-acetyl-2-methoxymethyl-4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    as crystals (1.44 g).

IR ν (Nujol) cm⁻¹; 3253, 1684, 1649, 1585, 1520.

¹H-NMR (CDCl₃) δ (ppm); 1.26 (9H, s), 2.13 (3H, s), 2.16 (3H, s), 2.41(3H, s), 2.62 (1H, d, J=16.1 Hz), 3.26 (1H, dd, J=16.1, 8.3 Hz), 3.30(3H, s), 3.30-3.40 (2H, m), 4.65-4.70 (1H, m), 8.92 (1H, s).

-   (7) The compound (1.44 g) obtained in (6) was dissolved in ethanol    (14.4 mL), and 2M aqueous sodium hydroxide solution (4.77 mL) was    added. The mixture was stirred at 60° C. for 1 hr. The solvent was    evaporated under reduced pressure and the obtained residue was    dissolved in ethyl acetate (50 mL), washed successively with    saturated aqueous sodium hydrogencarbonate and saturated brine (each    50 mL) and dried over sodium sulfate. Ethyl acetate was evaporated    under reduced pressure and diisopropyl ether (20 mL) was added to    the obtained crystalline residue. The crystals were washed by    stirring the mixture and collected by filtration to give    N-(2-methoxymethyl-4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    as crystals (1.26 g).

IR ν (Nujol) cm⁻¹; 3369, 3282, 1639, 1600, 1518.

¹H-NMR (CDCl₃) δ (ppm); 1.35 (9H, s), 2.13 (3H, s), 2.15 (3H, s), 2.74(1H, dd, J=16.1, 6.4 Hz), 3.12 (1H, dd, J=16.1, 9.5 Hz), 3.35-3.45 (2H,m), 3.40 (3H, s), 4.10-4.20 (1H, m), 4.74 (1H, br-s), 6.99 (1H, s).

-   (8) The compound (1.25 g) obtained in (7) was dissolved in    N,N-dimethylformamide (6.25 mL), and diisopropylethylamine (0.95 mL)    and propyl iodide (0.73 mL) were added under a nitrogen atmosphere.    The mixture was stirred at 90° C. for 14 hr. Ethyl acetate (50 mL)    was added to the reaction mixture and the mixture was washed    successively with 5% aqueous citric acid, water and saturated brine    (each 50 mL) and dried over sodium sulfate. The obtained residue was    purified by silica gel column chromatography to give    N-(2-methoxymethyl-4,6-dimethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (840 mg).

IR ν (Nujol) cm⁻¹; 3279, 1647, 1591, 1508.

¹H-NMR (CDCl₃) δ (ppm); 0.85 (3H, t, J=7.3 Hz), 1.34 (9H, s), 1.40-1.60(2H, m), 2.02 (3H, s), 2.10 (3H, s), 2.66 (1H, dd, J=16.6, 5.6 Hz),3.00-3.10 (1H, m), 3.12 (1H, dd, J=16.6, 10.0 Hz), 3.35-3.45 (2H, m),3.38 (3H, s), 3.47 (1H, dd, J=9.3, 5.1 Hz), 3.85-3.90 (1H, m), 6.76 (1H,s).

-   (9) The compound (830 mg) obtained in (8) was dissolved in methanol    (16.6 mL) and 5% palladium-carbon (170 mg) was added. The mixture    was subjected to catalytic hydrogenation at 30° C., 3 kgf/cm² for 11    hr. Palladium-carbon was filtered off, and the solvent was    evaporated under reduced pressure. To the obtained crystalline    residue was added diisopropyl ether (20 mL), and the crystals were    washed by stirring the mixture and collected by filtration to give    N-(5-amino-2-methoxymethyl-4,6-dimethyl-1-propylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (590 mg).

IR ν (Nujol) cm⁻¹; 3265, 1652, 1508.

¹H-NMR (CDCl₃) δ (ppm); 0.83 (3H, t, J=7.4 Hz), 1.34 (9H, s), 1.40-1.55(2H, m), 1.91 (3H, s), 2.04 (3H, s), 2.62 (1H, dd, J=16.1, 3.9 Hz),2.75-2.85 (1H, m), 2.90-3.00 (1H, m), 3.15-3.25 (2H, m), 3.32 (2H,br-s), 3.36 (3H, s), 3.38-3.44 (1H, m), 3.55-3.65 (1H, m), 6.94 (1H, s).

-   (10) tert-Butanol (0.295 mL) was dissolved in methylene chloride    (7.2 mL) and chlorosulfonyl isocyanate (0.27 mL) was added dropwise    at −10° C. The mixture was stirred at the same temperature for 20    min. A solution of the compound (540 mg) obtained in (9) in    methylene chloride (7.2 mL) and triethylamine (0.43 mL) were added,    and the mixture was stirred at the same temperature for 15 min.    Ethyl acetate (50 mL) was added to the reaction mixture and the    mixture was washed successively with 5% aqueous citric acid, 5%    aqueous sodium hydrogencarbonate and saturated brine (each 50 mL)    and dried over sodium sulfate. The solvent was evaporated under    reduced pressure and the obtained residue was purified by silica gel    column chromatography to give    N-[5-(N-tert-butoxycarbonyl)sulfamoylamino-2-methoxymethyl-4,6-dimethyl-1-propylindolin-7-yl]-2,2-dimethylpropanamide    (560 mg).

IR ν (Nujol) cm⁻¹; 3285, 1728, 1654, 1597.

¹H-NMR (CDCl₃) δ (ppm); 0.83 (3H, d, J=7.4 Hz), 1.33 (9H, s), 1.40-1.60(2H, m), 1.50 (9H, s), 2.08 (3H, s), 2.17 (3H, s), 2.61 (1H, dd, J=16.3,6.1 Hz), 2.95-3.05 (1H, m), 3.13 (1H, dd, J=16.3, 10.2 Hz), 3.25-3.30(1H, m), 3.30-3.35 (1H, m), 3.37 (3H, s), 3.47 (1H, dd, J=9.5, 5.4 Hz),3.75-3.85 (1H, m), 6.45 (1H, s), 6.84 (1H, s), 7.52 (1H, br-s).

-   (11) The compound (550 mg) obtained in (10) was dissolved in formic    acid (2.2 mL), and 8.7 M hydrogen chloride—2-propanol solution (0.38    mL) was added under ice-cooling. The mixture was stirred at the same    temperature for 20 min. Diethyl ether (50 mL) was added and the    precipitated crystals were collected by filtration to give the title    compound as crystals (330 mg).

IR ν (Nujol) cm⁻¹; 3321, 3204, 1649, 1527.

¹H-NMR (DMSO-d₆) δ (ppm); 0.80 (3H, t, J=7.3 Hz), 1.26 (9H, s),1.40-1.70 (2H, m), 2.09 (3H, s), 2.20 (3H, s), 2.60-2.80 (1H, m),2.95-3.05 (1H, m), 3.20-3.35 (2H, m), 3.30 (3H, s), 3.40-3.55 (2H, m),3.50-4.50 (4H, m), 8.20-8.50 (1H, br), 9.00-9.40 (1H, br).

According to Example 50, the compound of Example 51 was synthesized.

Example 51N-(2-ethoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3322, 3197, 2789, 2716, 1652, 1532, 1323, 1218, 1197,1155, 1123.

¹H-NMR (DMSO-d₆) δ (ppm); 0.82 (3H, t, J=7.1 Hz), 1.14 (3H, t, J=7.1Hz), 1.26 (9H, s), 1.45-1.65 (2H, m), 2.12 (3H, s), 2.21 (3H, s),2.63-2.78 (1H, m), 2.99 (0.5H, dd, J=10.3, 5.9 Hz), 3.02 (0.5H, dd,J=10.3, 6.4 Hz), 3.20-3.35 (2H, m), 3.50 (2H, d, J=7.1 Hz), 3.50 (2H, q,J=7.1 Hz), 3.50-4.60 (3H, br), 6.60-7.00 (1H, br), 8.20-8.45 (1H, br),9.05-9.40 (1H, m).

Example 52N-(1-butyryl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide

-   (1) N-(4,6-Dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    (1.0 g) was dissolved in chloroform (10 mL), and triethylamine (0.69    mL) and butyryl chloride (0.52 mL) were added under ice-cooling. The    mixture was stirred at the same temperature for 15 min. Ethyl    acetate (100 mL) was added to the reaction mixture, and the mixture    was washed successively with 5% aqueous citric acid, water and    saturated brine (each 100 mL) and dried over sodium sulfate. Ethyl    acetate was evaporated under reduced pressure and the obtained    residue was purified by silica gel column chromatography to give    N-(1-butyryl-4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    as crystals (0.94 g).

IR ν (Nujol) cm⁻¹; 3194, 1670, 1645, 1583, 1529.

¹H-NMR (CDCl₃) δ (ppm); 1.03 (3H, t, J=7.2 Hz), 1.27 (9H, s), 1.50-2.00(2H, m), 2.10 (3H, s), 2.15 (3H, s), 2.52 (2H, t, J=7.7 Hz), 2.90-3.20(2H, m), 4.16 (2H, br-t), 9.05 (1H, b-s).

-   (2) The compound (0.9 g) obtained in (1) was dissolved in methanol    (20 mL), 5% palladium-carbon (200 mg) was added. The mixture was    subjected to catalytic hydrogenation at 35° C., 3 kgf/cm² for 11 hr.    Palladium-carbon was filtered off, and the solvent was evaporated    under reduced pressure. Diethyl ether (20 mL) was added to the    obtained crystalline residue, and the crystals were washed by    stirring the mixture and collected by filtration to give    N-(5-amino-1-butyryl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (0.79 g).

IR ν (Nujol) cm⁻¹; 3356, 3192, 1676, 1626, 1593.

¹H-NMR (CDCl₃) δ (ppm); 1.02 (3H, t, J=7.3 Hz), 1.28 (9H, s), 1.50-2.00(2H, m), 1.97 (3H, s), 2.05 (3H, s), 2.48 (2H, t, J=6.8 Hz), 2.80-3.20(2H, m), 3.57 (2H, br-s), 3.80-4.20 (2H, m), 9.37 (1H, br-s).

-   (3)    N-[5-(N-tert-Butoxycarbonyl)sulfamoylamino-1-butyryl-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (548 mg) by treating in the same manner as    in Example, 50 (10) using the compound (400 mg) obtained in (2).

IR ν (Nujol) cm⁻¹; 3283, 3141, 1741, 1720, 1676, 1625, 1583.

¹H-NMR (CDCl₃) δ (ppm); 1.02 (3H, t, J=7.6 Hz), 1.26 (9H, s), 1.51(9H,s), 1.50-1.90 (2H, m), 2.19 (3H, s), 2.29 (3H, s), 2.45-2.55 (2H, m),2.70-2.90, 3.10-3.40 (2H, br, br), 3.95-4.10, 4.15-4.30 (2H, br, br),6.60 (1H, br-s), 7.50-7.80 (1H, s), 9.19 (1H, s).

-   (4) The title compound was obtained as crystals (618 mg) by treating    in the same manner as in Example 6 using the compound (1.36 g)    obtained in (3).

IR ν (Nujol) cm⁻¹; 3315, 3217, 1666, 1627, 1583.

¹H-NMR (DMSO-d₆) δ (ppm); 0.96 (3H, t, J=7.3 Hz), 1.17 (9H, s),1.55-1.70 (2H, m), 2.12 (3H, s), 2.24 (3H, s), 2.45-2.60 (2H, m),2.75-3.20 (2H, br), 3.80-4.10, 4.20-4.40 (2H, br, br), 6.72 (2H, s),8.36 (1H, br-s), 9.07 (1H, s).

Example 53N-(2,4,6-trimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

-   (1) 1-Acetyl-2,4,6-trimethylindoline was obtained as crystals (520    mg) by treating in the same manner as in Example 1 (1) using    2,4,6-trimethylindole (480 mg).

IR ν (Nujol) cm⁻¹; 1653, 1593.

¹H-NMR (CDCl₃) δ (ppm); 1.28 (3H, d, J=6.4 Hz), 2.19 (3H, s), 2.30 (6H,s), 2.40-3.40 (2H, m), 4.52 (1H, br), 6.83 (1H, s), 7.81 (1H, s).

-   (2) 1-Acetyl-5-bromo-2,4,6-trimethylindoline (10.85 g) was obtained    by treating in the same manner as in Example 50 (3) using the    compound (8.3 g) obtained in (1).

IR ν (Nujol) cm⁻¹; 3651, 1655.

¹H-NMR (CDCl₃) δ (ppm); 1.29 (3H, d, J=6.4 Hz), 2.30 (6H, s), 2.41 (3H,s), 2.47-3.48 (2H, m), 4.54 (1H, br), 7.95 (1H, s).

-   (3) 1-Acetyl-5-bromo-2,4,6-trimethyl-7-nitroindoline was obtained as    crystals (440 mg) by treating in the same manner as in Example    50 (4) using the compound (540 mg) obtained in (2).

IR ν (Nujol) cm⁻¹; 1676, 1533.

¹H-NMR (CDCl₃) δ (ppm); 1.37 (3H, d, J=6.6 Hz), 2.23 (3H, s), 2.36 (3H,s), 2.48 (3H, s), 2.48-3.54 (2H, m), 4.48-4.64 (1H, m).

-   (4) N-(1-Acetyl-2,4,6-trimethylindolin-7-yl)-2,2-dimethylpropanamide    (951 mg) was obtained by treating in the same manner as in Example    50 (5) using the compound (1.0 g) obtained in (3).

IR ν (Nujol) cm⁻¹; 3242, 1645.

¹H-NMR (CDCl₃) δ (ppm); 1.27 (3H, d, J=6.6 Hz), 1.27 (9H, s), 2.18 (6H,s), 2.30 (3H, s), 2.35-3.45 (2H, m), 4.44-4.59 (1H, m), 6.88 (1H, s),8.98 (1H, br).

-   (5)    N-(1-Acetyl-2,4,6-trimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    was obtained as crystals (6.68 g) by treating in the same manner as    in Example 50 (6) using the compound (6.94 g) obtained in (4).-   (6) N-(2,4,6-Trimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    (2.56 g) was obtained by treating in the same manner as in Example    50 (7) using the compound (3.0 g) obtained in (5).

IR ν (Nujol) cm⁻¹; 3269, 1643, 1519.

¹H-NMR (CDCl₃) δ (ppm); 1.29 (3H, d, J=6.6 Hz), 1.27 (9H, s), 2.11 (3H,s), 2.12 (3H, s), 2.33 (3H, s), 2.40-3.40 (2H, m), 4.40-4.60 (1H, m),4.58 (1H, s), 7.03 (1H, s), 8.97 (1H, s).

-   (7)    N-(2,4,6-Trimethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (710 mg) was obtained by treating in the same manner as    in Example 50 (8) using the compound (700 mg) obtained in (6).

IR ν (Nujol) cm⁻¹; 3274, 1651, 1593, 1512.

¹H-NMR (CDCl₃) δ (ppm); 0.88 (3H, t, J=7.3 Hz), 1.26 (3H, d, J=6.1 Hz),1.34 (9H, s), 1.40-1.65 (2H, m), 2.03 (3H, s), 2.10 (3H, s), 2.44 (1H,dd, J=16.1, 7.1 Hz), 2.95-3.05 (1H, m), 3.16 (1H, dd, J=16.1, 9.5 Hz),3.35-3.45 (1H, m), 3.75-3.85 (1H, m), 6.73 (1H, s).

-   (8) The compound (686 mg) obtained in (7) was dissolved in methanol    (15 mL), 5% palladium-carbon (170 mg) was added. The mixture was    subjected to catalytic hydrogenation at 30° C., 3 kgf/cm² for 11 hr.    Palladium-carbon was filtered off, and the solvent was evaporated    under reduced pressure. Diisopropyl ether (20 mL) was added to the    obtained crystalline residue and the crystals were washed by    stirring the mixture and collected by filtration to give    N-(5-amino-2,4,6-trimethyl-1-propylindolin-7-yl)-2,2-dimethylpropanamide    as crystals (513 mg). tert-Butanol (0.18 mL) was dissolved in    methylene chloride (1.8 mL) and chlorosulfonyl isocyanate (0.16 mL)    was added dropwise at −10° C. The mixture was stirred at the same    temperature for 20 min. The crystals (500 mg) obtained earlier and    triethylamine (0.26 mL) were added, and the mixture was stirred at    the same temperature for 1 hr. Ethyl acetate (50 mL) was added to    the reaction mixture and the mixture was washed successively with 5%    aqueous citric acid, 5% aqueous sodium hydrogencarbonate and    saturated brine (each 50 mL) and dried over sodium sulfate. The    solvent was evaporated under reduced pressure and the obtained    residue was purified by silica gel column chromatography to give    N-[5-(N-tert-butoxycarbonyl)sulfamoylamino-2,4,6-trimethyl-1-propylindolin-7-yl]-2,2-dimethylpropanamide    (680 mg).

IR ν (Nujol) cm⁻¹; 3283, 3233, 1726, 1651, 1514.

¹H-NMR (DMSO-d₆) δ (ppm); 0.79 (3H, t, J=7.1 Hz), 1.19 (3H, d, J=6.4Hz), 1.22 (9H, s), 1.30-1.50 (2H, m), 1.43 (9H, s), 1.95 (3H, s), 2.05(3H, s), 2.25-2.35 (1H, m), 2.85-2.95 (1H, m), 3.00-3.15 (1H, m),3.20-3.40 (1H, m), 3.60-3.75 (1H, br), 8.65 (1H, s), 9.11 (1H, s), 10.77(1H, br-s).

-   (9) The title compound obtained was obtained as crystals (384 mg) by    treating in the same manner as in Example 6 using the compound (660    mg) obtained in (8)

IR ν (Nujol) cm⁻¹; 3204, 1666, 1504.

¹H-NMR (DMSO-d₆) δ (ppm); 0.83 (3H, t, J=7.1 Hz), 1.29 (9H, s), 1.39(3H, d, J=6.1 Hz), 1.50-1.90 (2H, m), 2.12 (3H, s), 2.26 (3H, s),2.65-2.80 (1H, m), 2.95-3.05 (1H, m), 3.20-3.30 (1H, m), , 3.35-4.00(2H, m), 4.15-4.40 (1H, br), 6.50-7.50 (2H, br), 8.49 (1H, br-s),9.30-9.70 (1H, br).

According to Example 53, the compounds of Examples 54 and 55 weresynthesized.

Example 54N-[1-(2-ethoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3366, 3279, 1655, 1626, 1522, 1329, 1194, 1157.

¹H-NMR (DMSO-d₆) δ (ppm); 1.12 (3H, t, J=7.1 Hz), 1.26 (9H, s), 1.34(3H, d, J=5.9 Hz), 2.10 (3H, s), 2.22 (3H, s), 2.50-2.69 (1H, m),3.16-3.28 (1H, m), 3.28-3.72 (7H, m), 3.72-4.60 (2H, br), 6.40-7.20 (1H,br), 8.25-8.50 (1H, br), 9.10-9.35 (1H, m).

Example 55N-[1-(2-methoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻1; 3339, 3258, 3180, 3040, 1653, 1624, 1528, 1339, 1165.

¹H-NMR (DMSO-d₆) δ (ppm); 1.25 (9H, s), 1.34 (3H, d, J=6.1 Hz), 2.10(3H, s), 2.22 (3H, s), 2.50-2.69 (1H, m), 3.15-3.70 (6H, m), 3.26 (3H,s), 3.40-4.70 (2H, br), 6.20-7.20 (1H, br), 8.25-8.50 (1H, br),9.10-9.35 (1H, m).

Example 56N-[3-(2-methoxyethyl)-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

-   (1) 4,6-Dimethyltryptophol (16.53 g) was dissolved in acetic acid    (83 mL), and, sodium cyanoborohydride (10.7 g) was added in portions    at 10° C. The mixture was stirred at the same temperature for 1 hr.    A solution of sodium hydroxide (60 g) in water (200 mL) was added    dropwise, and the mixture was extracted with ethyl acetate (1 L),    washed successively with water and saturated brine (each 500 mL) and    dried over sodium sulfate. Ethyl acetate was evaporated under    reduced pressure to give 3-(2-hydroxyethyl)-4,6-dimethylindoline as    crystals (16.34 g). The obtained crystal (16.34 g) were dissolved in    tetrahydrofuran (160 mL) and di-tert-butyl dicarbonate (22.39 g) was    added. The mixture was stirred at room temperature for 2 hr.    Tetrahydrofuran was evaporated under reduced pressure and the    obtained residue was purified by silica gel column chromatography to    give 1-tert-butoxycarbonyl-3-(2-hydroxyethyl)-4,6-dimethylindoline    (22.14 g).

IR ν (Nujol) cm⁻¹; 3439, 1739, 1705, 1596.

¹H-NMR (CDCl₃) δ (ppm); 1.56 (9H, s), 1.37 (1H, br-s), 1.65-1.77 (1H,m), 1.85-1.95 (1H, m), 2.25 (3H, s), 2.29 (3H, s), 3.30-3.40 (1H, m),3.70-3.80 (2H, m), 3.80-3.95 (2H, m), 6.60 (1H, s), 7.10-7.70 (1H, br).

-   (2) The compound (22.1 g) obtained in (1) and methyl iodide (9.47    mL) were dissolved in N,N-dimethylformamide (110 mL), and sodium    hydride (60% oil suspension) (3.92 g) was added in portions under    ice-cooling. The mixture was stirred at the same temperature for 30    min and ethyl acetate (500 mL) was added. The mixture was washed    successively with 5% aqueous citric acid, water and saturated brine    (each 500 mL) and dried over sodium sulfate. Ethyl acetate was    evaporated under reduced pressure to give    1-tert-butoxycarbonyl-3-(2-methoxyethyl)-4,6-dimethylindoline (22.8    g).

IR ν (Nujol) cm⁻; 1741, 1705.

¹H-NMR (CDCl₃) δ (ppm); 1.57 (9H, s), 1.60-1.70 (1H, m), 1.90-2.00 (1H,m), 2.24 (3H, s), 2.29 (3H, s), 3.25-3.35 (1H, m), 3.34 (3H, s),3.35-3.45 (2H, m), 3.80-3.90 (2H, m), 6.60 (1H, s), 7.10-7.70 (1H, br).

-   (3) The compound (22.7 g) obtained in (2) was dissolved in formic    acid (72 mL), and 8.7 M hydrogen chloride—2-propanol solution (29    mL) was added under ice-cooling. The mixture was stirred at the same    temperature for 15 min. A mixture (500 mL) of n-hexane-diisopropyl    ether (5-1) was added, and an oil was separated. The obtained oil    was dissolved in water (500 mL) and the mixture was neutralized with    sodium bicarbonate. The mixture was extracted with ethyl acetate    (500 mL), successively with water and saturated brine (each 500 mL)    and dried over sodium sulfate. Ethyl acetate was evaporated under    reduced pressure to give 3-(2-methoxyethyl)-4,6-dimethylindoline as    an oil (14.0 g). The obtained oil was dissolved in chloroform (155    mL) and acetic anhydride (10.7 mL) and triethylamine (15.8 mL) were    added under ice-cooling. The mixture was stirred at room temperature    for 1 hr. The reaction mixture was washed successively with 5%    aqueous citric acid, 5% aqueous sodium hydrogencarbonate and    saturated brine (each 200 mL) and dried over sodium sulfate.    Chloroform was evaporated under reduced pressure and the obtained    residue was purified by silica gel column chromatography to give    1-acetyl-3-(2-methoxyethyl)-4,6-dimethylindoline as an oil (19.7 g).

IR ν (Nujol) cm⁻1; 1662, 1593.

¹H-NMR (CDCl₃) δ (ppm); 1.60-1.75 (1H, m), 1.85-2.00 (1H, m), 2.22 (3H,s), 2.25 (3H, s), 2.31 (3H, s), 3.20-3.35 (1H, m), 3.32 (3H, s),3.35-3.45 (2H, m), 3.85-3.95 (1H, m), 3.95-4.05 (1H, m), 6.68 (1H, s),7.89 (1H, s).

-   (4) 1-Acetyl-5-bromo-3-(2-methoxyethyl)-4,6-dimethylindoline    (26.7 g) was obtained by treating in the same manner as in Example    50 (3) using the compound (19.6 g) obtained in (3)

IR ν (Nujol) cm⁻¹; 1645, 1581.

¹H-NMR (CDCl₃) δ (ppm); 1.60-1.75 (1H, m), 1.85-1.95 (1H, m), 2.21 (3H,s), 2.33 (3H, s), 2.40 (3H, s), 3.32 (3H, s), 3.35-3.50 (3H, m),3.90-4.10 (2H, m), 8.00 (1H, s).

-   (5) 1-Acetyl-5-bromo-3-(2-methoxyethyl)-4,6-dimethyl-7-nitroindoline    was obtained as crystals (19.4 g) by treating in the same manner as    in Example 50 (4).using-the compound (26.6 g) obtained in (4).

IR ν (Nujol) cm⁻¹; 1737, 1681, 1533.

¹H-NMR (CDCl₃) δ (ppm); 1.65-1.75 (1H, m), 1.80-1.90 (1H, m), 2.23 (3H,s), 2.39 (3H, s), 2.48 (3H, s), 3.25-3.45 (3H, m), 3.30 (3H, s),4.10-4.20 (2H, m).

-   (6)    N-[1-Acetyl-3-(2-methoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide    (9.09 g) was obtained by treating in the same manner as in Example    50 (5) using the compound (10 g) obtained in (5).

IR ν (Nujol) cm⁻¹; 3234, 1668, 1641, 1585.

¹H-NMR (CDCl₃) δ (ppm); 1.27 (9H, s), 1.65-1.80 (1H, m), 1.85-1.95 (1H,m), 2.18 (3H, s), 2.21 (3H, s), 2.28 (3H, s), 3.15-3.25 (1H, m), 3.29(3H, s), 3.30-3.35. (1H, m), 3.35-3.45 (1H, m), 4.05-4.15 (2H, m), 6.88(1H, s), 9.07 (1H, br-s).

-   (7)    N-[l-Acetyl-3-(2-methoxyethyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    as crystals (10.96 g) was obtained by treating in the same manner as    in Example 50 (6) using the compound (9.0 g) obtained in (6).

IR ν (Nujol) cm⁻¹; 3219, 1683, 1649, 1583, 1529.

¹H-NMR (CDCl₃) δ (ppm); 1.27 (9H, s), 1.70-1.80 (1H, m), 1.85-1.95 (1H,m), 2.11 (3H, s), 2.22 (3H, s), 2.31 (3H, s), 3.20-3.35 (2H, m), 3.28(3H, s), 3.40-3.45 (1H, m), 4.05-4.25 (2H, m), 9.09 (1H, br-s).

-   (8)    N-[3-(2-Methoxyethyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (6.08 g) by treating in the same manner as    in Example 50 (7) using the compound (9.3 g) obtained in (7).

IR ν (Nujol) cm⁻¹; 3420, 3282, 1647, 1610, 1595.

¹H-NMR (CDCl₃) δ (ppm); 1.35 (9H, s), 1.70-1.90 (2H, m), 2.14 (3H, s),2.22 (3H, s), 3.34 (3H, s), 3.35-3.50 (4H, m), 3.69 (1H, d, J=9.5 Hz),4.49 (1H, br-s), 7.03 (1H, br-s).

-   (9)    N-[3-(2-Methoxyethyl)-4,6-dimethyl-5-nitro-1-propylindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (1.44 g) by treating in the same manner as    in Example 50 (8) using the compound (1.5 g) obtained in (8).

IR ν (Nujol) cm⁻¹; 3271, 1651, 1591, 1514.

¹H-NMR (CDCl₃) δ (ppm); 0.91 (3H, t, J=7.3 Hz), 1.34 (9H, s), 1.45-1.60(2H, m), 1.65-1.75 (1H, m), 1.75-1.85 (1H, m), 2.03 (3H, s), 2.17 (3H,s), 3.05-3.15 (1H, m), 3.25-3.50 (5H, m), 3.33 (3H, s), 3.52 (1H, t,J=9.3 Hz), 6.76 (1H, br-s).

-   (10)    N-[5-Amino-3-(2-methoxyethyl)-4,6-dimethyl-1-propylindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (1.3 g) by treating in the same manner as    in Example 50 (9) using the compound (1.4 g) obtained in (9).

¹H-NMR (CDCl₃) δ (ppm); 0.89 (3H, t, J=7.3 Hz), 1.35 (9H, s), 1.45-1.60(2H, m), 1.50-2.00 (2H, m), 1.60-1.70 (1H, m), 1.80-1.90 (1H, m), 1.93(3H, s), 2.10 (3H, s), 2.75-2.85 (1H, m), 3.10-3.20 (1H, m), 3.20-3.30(2H, m), 3.35 (3H, s), 3.35-3.50 (3H, m), 6.93 (1H, br-s).

-   (11)    N-[5-(N-tert-Butoxycarbonyl).sulfamoylamino-3-(2-methoxyethyl)-4,6-dimethyl-1-propylindolin-7-yl]-2,2-dimethylpropanamide    (1.77 g) was obtained by treating in the same manner as in Example    50 (10) using the compound (1.25 g) obtained in (10).

IR ν (Nujol) cm⁻¹; 3294, 1728, 1655, 1595.

¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, t, J=7.3 Hz), 1.33 (9H, s) 1.40-1.80(4H, m), 1.50 (9H, s), 2.09 (3H, s), 2.24 (3H, s), 2.95-3.05 (1H, m),3.20-3.50 (6H, m), 3.33 (3H, s), 6.47 (1H, s), 6.87 (1H, s).

-   (12) The title compound was obtained as crystals (1.08 g) by    treating in the same manner as in Example 6 using the compound    (1.7 g) obtained in (11).

IR ν (Nujol) cm⁻; 3280, 3093, 1678.

¹H-NMR (DMSO-d₆) δ (ppm); 0.87 (3H, t, J=7.3 Hz), 1.27 (9H, s),1.60-1.80 (3H, m), 1.90-2.00 (1H, m), 2.12 (3H, s), 2.31 (3H, s),3.00-3.10 (1H, m), 3.20-3.30 (1H, m), 3.27 (3H, s), 3.30-3.80 (5H, m),6.50-7.50 (2H, m), 8.45 (1H, br-s), 9.16 (1H, br-s).

Example 57N-(4,6-dimethyl-2-methylthiomethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

-   (1) 4,6-Dimethyl-2-hydroxymethylindole (14.5 g) was dissolved in    acetic acid (145 mL) and sodium cyanoborohydride (11.6 g) was added    in portions at 10° C. The mixture was stirred at the same    temperature for 1 hr. A solution of sodium hydroxide (101 g) in    water (400 mL) was added dropwise and the mixture was extracted with    ethyl acetate (1 L). The extract was washed successively with water    and saturated brine (each 500 mL) and dried over sodium sulfate.    Ethyl acetate was evaporated under reduced pressure to give    2-hydroxymethyl-4,6-dimethylindoline as an oil (13.8 g). The    obtained oil was dissolved in chloroform (138 mL), and acetic    anhydride (22 mL) and triethylamine (32.6 mL) were added under    ice-cooling. The mixture was stirred at room temperature for 2 days.    The reaction mixture was washed successively with 5% aqueous citric    acid, water and saturated brine (each 200 mL) and dried over sodium    sulfate. Chloroform was evaporated under reduced pressure to give    2-acetoxymethyl-1-acetyl-4,6-dimethylindoline as an oil (18.3 g).

¹H-NMR (CDCl₃) δ (ppm); 2.00 (3H, s), 2.19 (3H, s), 2.31 (3H, s), 2.36(3H, s), 2.70 (1H, d, J=16.0 Hz), 3.15 (1H, dd, J=16.0, 8.6 Hz),3.80-4.30 (2H, m), 4.40-5.20 (1H, m), 6.69 (1H, s), 7.40-8.00 (1H, br).

-   (2) 2-Acetoxymethyl-1-acetyl-5-bromo-4,6-dimethylindoline (9.46 g)    was obtained by treating in the same manner as in Example 50 (3)    using the compound (7.43 g) obtained in (1).

IR ν (Nujol) cm⁻¹; 1747, 1660, 1651.

¹H-NMR (CDCl₃) δ (ppm); 1.95 (0.9H, br-s), 2.06 (2.1H, br-s), 2.31 (3H,s), 2.35 (3H, s), 2.41 (3H, s), 2.70-2.90 (1H, m), 3.10-3.30 (1H, m),3.90 (0.6H, br-s), 4.19 (1.4H, br-s), 4.62 (0.7H, br-s), 4.90-5.20(0.3H, br), 6.80-7.00 (0.3H, br), 7.91 (0.7H, br-s).

-   (3) 2-Acetoxymethyl-1-acetyl-5-bromo-4,6-dimethyl-7-nitroindoline    was obtained as crystals (10.04 g) by treating in the same manner as    in Example 50 (4) using the-compound (9.34 g) obtained in (2).

IR ν (Nujol) cm⁻¹; 1744, 1672, 1537.

¹H-NMR (CDCl₃) δ (ppm); 2.09 (3H, s), 2.31 (3H, s), 2.38 (3H, s), 2.50(3H, s), 2.81 (1H, d, J=16.1 Hz), 3.31 (1H, dd, J=16.1, 8.6 Hz), 4.00(1H, dd, J=11.5, 7.1 Hz), 4,26 (1H, dd, J=11.5, 6.8 Hz), 4.70-4.80 (1H,m).

-   (4)    N-(2-Acetoxymethyl-1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide    (7.7 g) was obtained by treating in the same manner as in Example    50 (5) using the compound (10.0 g) obtained in (3).

IR ν (Nujol) cm⁻¹; 3265, 1740, 1674, 1639, 1587.

¹H-NMR (CDCl₃) δ (ppm); 1.26 (9H, s), 2.01 (3H, s), 2.18 (3H, s), 2.19(3H, s), 2.38 (3H, s), 2.65 (1H, d, J=15.9 Hz), 3.25 (1H, dd, J=15.9,8.3 Hz), 4.00-4.15 (2H, m), 4.60-4.70 (1H, m), 6.90 (1H, s), 8.84 (1H,br-s).

-   (5)    N-(2-Acetoxymethyl-1-acetyl-4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    was obtained as crystals (7.92 g) by treating in the same manner as    in Example 50 (6) using the compound (7.7 g) obtained in (4).

IR ν (Nujol) cm⁻¹; 3284, 1735, 1685, 1639, 1585.

¹H-NMR (CDCl₃) δ (ppm); 1.26 (9H, s), 1.99 (3H, s), 2.12 (3H, s), 2.18(3H, s), 2.41 (3H, s), 2.65 (1H, d, J=15.9 Hz), 3.34 (1H, dd, J=15.9,8.0 Hz), 4.12 (2H, d, J=6.3 Hz), 4.65-4.75 (1H, m), 8.82 (1H, b-s).

-   (6) The compound (7.87 g) obtained in (5) was dissolved in methanol    (79 mL), and 1M aqueous solution of lithium hydroxide (29.1 mL) was    added under ice-cooling. The mixture was stirred at the same    temperature for 30 min. Chloroform (300 mL) was added to the    reaction mixture and the mixture was washed successively with 10%    aqueous citric acid, saturated aqueous sodium hydrogencarbonate and    saturated brine (each 300 mL) and dried over sodium sulfate.    Chloroform was evaporated under reduced pressure to give    N-(2-hydroxymethyl-4,6-dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    as crystals (5.7 g).

IR ν (Nujol) cm⁻¹; 3273, 1651, 1597, 1515.

¹H-NMR (CDCl₃) δ (ppm); 1.36 (9H, s), 2.14 (3H, s), 2.15 (3H, s),2.40-2.50 (1H, m), 2.80 (1H, dd, J=16.1, 5.6 Hz), 3.12 (1H, dd, J=16.1,9.5 Hz), 3.50-3.60 (1H, m), 3.68 (1H, dd, J=11.2, 4.2 Hz), 4.05-4.15(1H, m), 4.70 (1H, br-s), 7.12 (1H, br-s).

-   (7) The compound (5.34 g) obtained in (6) was dissolved in    N,N-dimethylformamide (26 mL), and diisopropylethylamine (8.48 mL)    and propyl iodide (6.48 mL) were added under a nitrogen atmosphere.    The mixture was stirred at 110° C. for 13 hr. Ethyl acetate (200 mL)    was added to the reaction mixture and the mixture was washed    successively with 5% aqueous citric acid, water and saturated brine    (each 200 mL) and-dried over sodium sulfate. Ethyl acetate was    evaporated under reduced pressure and the obtained residue was    purified by silica gel column chromatography to give    N-(2-hydroxymethyl-4,6-dimethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    (3.72 g).

IR ν (Nujol) cm⁻¹; 3307, 1739, 1651, 1591, 1506.

¹H-NMR (CDCl₃) δ (ppm); 0.85 (3H, t, J=7.3 Hz), 1.35 (9H, s), 1.40-1.55(2H, m), 2.07 (3H, s), 2.12 (3H, s), 2.76 (1H, dd, J=16.1, 4.4 Hz),2.85-3.00 (2H, m), 3.10-3.30 (2H, m), 3.40-3.50 (1H, m), 3.70-3.90 (2H,m), 6.94 (1H, b-s).

-   (8) The compound (3.7 g) obtained in (7) was dissolved in chloroform    (37 mL), and methanesulfonyl chloride (1.57 mL) and triethylamine    (2.84 mL) were added under ice-cooling. The mixture was stirred at    the same temperature for 30 min. The reaction mixture was washed    successively with 10% aqueous citric acid, saturated aqueous sodium    hydrogencarbonate and saturated brine (each 50 mL) and dried over    sodium sulfate. Chloroform was evaporated under reduced pressure and    the obtained residue was purified by silica gel column    chromatography to give    N-(2-methanesulfonyloxymethyl-4,6-dimethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    as an oil (1.82 g). The obtained oil was dissolved in    N,N-dimethylformamide (36 mL), and potassium thioacetate (942 mg)    was added. The mixture was stirred at 70° C. for 1 hr. Ethyl acetate    (200 mL) was added to the reaction mixture and the mixture was    washed successively with water and saturated brine (each 200 mL) and    dried over sodium sulfate. Ethyl acetate was evaporated under    reduced pressure to give    N-(2-acetylthiomethyl-4,6-dimethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    (1.39 g).

IR ν (Nujol) cm⁻¹; 3319, 1695, 1651, 1593, 1512.

¹H-NMR (CDCl₃) 6; (ppm); 0.87 (3H, t, J=7.3 Hz), 1.34 (9H, s), 1.40-1.60(2H, m), 2.03 (3H, s), 2.10 (3H, s), 2.37 (3H, s), 2.55 (1H, dd, J=16.4,4.9 Hz), 2.85 (1H, dd, J=13.7, 7.8 Hz), 3.00-3.10 (1H, m), 3.20 (1H, dd,J=16.4, 10.0 Hz), 3.24 (1H, dd, J=13.7, 4.1 Hz), 3.30-3.40 (1H, m),3.80-3.90 (1H, m), 6.76 (1H, br-s).

-   (9) The compound (690 mg) obtained in (8) was dissolved in methanol    (20.7 mL), and 1M aqueous sodium hydroxide solution (1.96 mL) was    added under ice-cooling. The mixture was stirred at the same    temperature for 1 hr. Ethyl acetate (100 mL) was added to the    reaction mixture and the mixture was washed successively with water    and saturated brine (each 100 mL) and dried over sodium sulfate.    Ethyl acetate was evaporated under reduced pressure to give    N-(2-mercaptomethyl-4,6-dimethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    (570 mg).

IR ν (Nujol) cm⁻¹; 3288, 1651, 1593, 1516.

¹H-NMR (CDCl₃) δ (ppm); 0.86 (3H, t, J=7.3 Hz), 1.34 (9H, s), 1.40-1.65(2H, m), 1.50-1.80 (1H, br), 2.04 (3H, s), 2.12 (3H, s), 2.60-2.75 (2H,m), 2.79 (1H, dd, J=16.6, 5.2 Hz), 2.90-3.00 (1H, m), 3.21 (1H, dd,J=16.6, 10.0 Hz), 3.30-3.40 (1H, m), 3.85-3.95 (1H, m), 6.77 (1H, br-s).

-   (10) The compound (550 mg) obtained in (9) was dissolved in    N,N-dimethylformamide (5.5 mL), and diisopropylethylamine (0.32 mL)    and methyl iodide (0.12 mL) were added under a nitrogen atmosphere.    The mixture was stirred at room temperature for 30 min. Ethyl    acetate (50 mL) was added to the reaction mixture and the mixture    was washed successively with water and saturated brine (each 50 mL)    and dried over sodium sulfate. Ethyl acetate was evaporated under    reduced pressure to give    N-(4,6-dimethyl-2-methylthiomethyl-5-nitro-1-propylindolin-7-yl)-2,2-dimethylpropanamide    (530 mg).

IR ν (Nujol) cm⁻¹; 3304, 1651, 1593, 1514.

¹H-NMR (CDCl₃) δ (ppm); 0.87 (3H, t, J=7.3 Hz), 1.34 (9H, s), 1.40-1.60(2H, m), 2.02 (3H, s), 2.12 (3H, s), 2.16 (3H, s), 2.57 (1H, dd, J=12.7,8.6 Hz), 2.70-2.80 (2H, m), 2.95-3.05 (1H, m), 3.23 (1H, dd, J=16.4, 9.7Hz), 3.35-3.45 (1H, m), 3.80-3.90 (1H, m), 6.77 (1H, br-s).

-   (11)    N-[5-(N-tert-Butoxycarbonyl)sulfamoylamino-4,6-dimethyl-2-methylthiomethyl-1-propylindolin-7-yl]-2,2-dimethylpropanamide    (430 mg) was obtained by treating in the same manner as in Example    53 (8) using the compound (520 mg) obtained in (10).

IR ν (Nujol) cm⁻¹; 3242, 1728, 1651, 1597, 1514.

¹H-NMR (DMSO-d₆) δ (ppm); 0.85 (3H, t, J=7.3 Hz), 1.33 (9H, s), 1.50(9H, s), 1.70-1.90 (2H, m), 2.09 (3H, s), 2.16 (3H, s), 2.19 (3H, s),2.55 (1H, dd, J=12.7, 8.8 Hz), 2.69 (1H, dd, J=16.4, 4.9 Hz), 2.75 (1H,dd, J=12.7, 4.2 Hz), 2.90-3.00 (1H, m), 3.20-3.35 (2H, m), 3.70-3.80(1H, m), 6.53 (1H, s), 6.89 (1H, s), 7.85-8.15 (1H, br).

-   (12) The title compound was obtained as crystals (327 mg) by    treating in the same manner as in Example 6 using the compound (410    mg) obtained in (11).

IR ν (Nujol) cm⁻¹; 3155, 1657, 1504, 1344, 1194, 1161.

¹H-NMR (DMSO-d₆) δ (ppm); 0.81 (3H, t, J=7.3 Hz), 1.26 (9H, s),1.42-1.70 (2H, m), 2.08 (3H, s), 2.14 (3H, s), 2.21 (3H, s), 2.57 (1H,dd, J=13.7, 8.8 Hz), 2.73-2.87 (1H, m), 2.89-3.06 (2H, m), 3.20-4.40(2H, br), 3.22-3.37 (2H, m), 4.00-4.15 (1H, m), 5.80-7.40 (1H, m),8.20-8.40 (1H, br), 9.00-9.20 (1H, br).

Example 58N-[1-(6-hydroxyhexyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

-   (1) N-(4,6-Dimethyl-5-nitroindolin-7-yl)-2,2-dimethylpropanamide    (3.15 g) was dissolved in N,N-dimethylformamide. (30 mL) and    diisopropylethylamine (2.2 mL) and 6-bromo-1-hexanol (1.7 mL) were    added under a nitrogen atmosphere. The mixture was stirred at    100° C. for 14 hr. Ethyl acetate (200 mL) was added to the reaction    mixture, and the mixture was washed successively with 5% aqueous    citric acid, water and saturated brine (each 100 mL) and dried over    sodium sulfate. Ethyl acetate was evaporated under reduced pressure    and the obtained residue was purified by silica gel column    chromatography to give    N-[1-(6-hydroxyhexyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    as crystals (1.6 g).

¹H-NMR (CDCl₃) δ (ppm); 1.25-1.45 (4H, m), 1.33 (9H, s), 1.45-1.60 (4H,m), 2.02 (3H, s), 2.11 (3H, s), 2.90 (2H, t, J=9.0 Hz), 3.24 (2H, t,J=7.6 Hz), 3.54 (2H, t, J=8.8 Hz), 3.60-3.70 (2H, m), 6.83 (1H, s).

-   (2) The compound (1.57 g) obtained in (1) was dissolved in    N,N-dimethylformamide (8 mL) and imidazole (600 mg) and    tert-butyldimethylsilyl chloride (664 mg) were added. The mixture    was stirred at room temperature for 0.5 hr. Ethyl acetate (200 mL)    was added to the reaction mixture, and the mixture was washed    successively with water and saturated brine (each 100 mL) and dried    over sodium sulfate. Ethyl acetate was evaporated under reduced    pressure and the obtained residue was purified by silica gel column    chromatography to give    N-[1-(6-tert-butyldimethylsilyloxyhexyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    (1.89 g).

IR ν (Nujol) cm⁻¹; 3290, 1647, 1593, 1508.

¹H-NMR (CDCl₃) δ (ppm); 0.05 (6H, s), 0.85 (9H, s), 1.10-1.70 (8H, m),1.29 (9H, s), 1.98 (3H, s), 2.06 (3H, s), 2.70-3.00 (2H, m), 3.10-3.30(2H, m), 3.30-3.70 (4H, m), 6.70 (1H, s).

-   (3) The compound (1.85 g) obtained in (2) was dissolved in methanol    (40 mL), and 5% palladium-carbon (370 mg) was added.

The mixture was subjected to catalytic hydrogenation at 35° C., 3kgf/cm² for 11 hr. Palladium-carbon was filtered off, and the solventwas evaporated under reduced pressure. Diethyl ether (20 mL) was addedto the obtained crystalline residue, and the crystals were washed bystirring the mixture and collected by filtration to giveN-(5-amino-1-(6-tert-butyldimethylsilyloxyhexyl)-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamideas crystals (1.60 g).

IR ν (Nujol) cm⁻1; 3284, 1657, 1506.

¹H-NMR (CDCl₃) δ (ppm); 0.05 (6H, s), 0.90 (9H, s), 1.10-1.70 (8H, m),1.35 (9H, s), 1.93 (3H, s), 2.06 (3H, s), 2.70-3.10 (4H, m), 3.00-3.80(2H, br), 3.20-3.50 (2H, m), 3.50-3.70 (2H, m), 6.92 (1H, s)

-   (4)    N-[5-(N-tert-Butoxycarbonyl)sulfamoylamino-1-(6-tert-butyldimethylsilyloxyhexyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide    (440 mg) was obtained by treating in the same manner as in Example 5    using the compound (400 mg) obtained in (3).

IR ν (Nujol) cm⁻¹; 3371, 3184, 1755, 1657, 1512.

¹H-NMR (CDCl₃) δ (ppm); 0.04 (6H, s), 0.81 (9H, s), 1.20-1.45 (4H, m),1.38 (9H, s), 1.40-1.70 (4H, m), 1.52 (9H, s), 2.06 (3H, s), 2.17 (3H,s), 2.83 (2H, t, J=8.3 Hz), 3.16 (2H, t, J=7.6 Hz), 3.40-3.50 (2H, m),3.58 (2H, t, J=6.6 Hz), 6.46 (1H, s), 6.92 (1H, s). 7.70-7.80 (1H, br).

-   (5) The title compound was obtained as crystals (650 mg) by treating    in the same manner as in Example 6 using the compound (1.35 g)    obtained in (4).

IR ν (Nujol) cm⁻¹; 3379, 3244, 3117, 1703, 1682, 1508.

¹H-NMR (DMSO-d₆) δ (ppm); 1.20-1.40 (4H, m), 1.28 (9H, s), 1.50-1.60(2H, m), 1.60-1.75 (2H, br), 2.13 (3H, s), 2.28 (3H, s), 3.05-3.25 (4H,m), 3.30-4.30 (1H, br), 3.70-3.85 (2H, m), 4.06 (2H, t, J=6.4 Hz),6.70-7.00 (2H, br), 8.19 (1H, s), 8.53 (1H, s), 9.24 (1H, s).

According to Example 57, the compound of Example 59 was synthesized.

Example 59N-(2-ethylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3146, 3063, 1651, 1504, 1339, 1192, 1159.

¹H-NMR (DMSO-d₆) δ (ppm); 0.81 (3H, t, J=7.2 Hz), 1.20 (3H, t, J=7.3Hz), 1.25 (9H, s), 1.40-1.70 (2H, m), 2.08 (3H, s), 2.21 (3H, s),2.50-2.70 (1H, m), 2.61 (2H, q, J=7.3 Hz), 2.70-2.90 (1H, m), 2.90-3.10(2H, m), 3.20-3.40 (2H, m), 3.40-4.40 (1H, br), 4.00-4.20 (1H, m),6.50-7.50 (2H, br), 8.30 (1H, br-s), 9.08 (1H, br-s).

Example 60N-[1-(2-ethylthioethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

-   (1)    N-[1-(2-Hydroxyethyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (6.21 g) by treating in the same manner as    in Example 50 (8) using the compound (8.0 g) obtained in Example    1 (6) and 2-bromoethanol (5.8 mL).

IR ν (Nujol) cm⁻¹; 3346, 3233, 1641, 1587, 1506.

¹H-NMR (DMSO-d₆) δ (ppm); 1.21 (9H, s), 1.87 (3H, s), 2.04 (3H, s), 2.89(2H, t, J=8.8 Hz), 3.30-3.40 (2H, m), 3.50-3.60 (2H, br), 4.65 (2H, t,J=8.8 Hz), 4.79 (1H, t, J=4.9 Hz), 8.85 (1H, s).

-   (2)    N-[1-(2-Acetylthioethyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (6.53 g) by treating in the same manner as    in Example 57 (8) using the compound (6.21 g) obtained in (1).

IR ν (Nujol) cm⁻; 3267, 1703, 1645, 1589, 1506.

¹H-NMR (CDCl₃) δ (ppm); 1.32 (9H, s), 2.05 (3H, s), 2.12 (3H, s), 2.35(3H, s), 2.94 (2H, t, J=9.0 Hz), 2.97 (2H, t, J=7.8 Hz), 3.35-3.45 (2H,m), 3.63 (2H, t, J=9.0 Hz), 7.07 (1H, s).

-   (3)    N-[1-(2-Mercaptoethyl)-4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    was obtained-as crystals (5.54 g) by treating in the same manner as    in Example 57 (9) using the compound (6.5 g) obtained in (2).

IR ν (Nujol) cm⁻¹; 3279, 1645, 1593, 1506.

¹H-NMR (CDCl₃) δ (ppm); 1.36 (9H, s), 1.43 (1H, t, J=7.0 Hz), 2.02 (3H,s), 2.11 (3H, s), 2.67 (2H, q, J=7.0 Hz), 2.94 (2H, t, , J=9.0 Hz), 3.50(2H, t, J=7.3 Hz), 3.57 (2H, t, J=9.0 Hz), 6.97 (1H, s).

-   (4) N-[1-(2-Ethylthioethyl)    −4,6-dimethyl-5-nitroindolin-7-yl]-2,2-dimethylpropanamide was    obtained as crystals (1.4 g) by treating in the same manner as in    Example 57 (10) using the compound (1.5 g) obtained in (3) and ethyl    iodide (0.65 mL).

IR ν (Nujol) cm⁻¹; 3277, 1645, 1591, 1510.

¹H-NMR (CDCl₃) δ (ppm); 1.25 (3H, t, J=7.4 Hz), 1.36 (9H, s), 2.03 (3H,s), 2.11 (3H, s), 2.55 (2H, q, J=7.4 Hz), 2.68 (2H, t, J=7.3 Hz), 2.93(2H, t, J=9.0 Hz), 3.51 (2H, t, J=7.3 Hz), 3.60 (2H, t, J=9.0 Hz), 7.00(1H, s).

-   (5)    N-[5-(N-tert-Butoxycarbonyl)sulfamoylamino-1-(2-ethylthioethyl)-4,6-dimethyl-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (940 mg) by treating in the same manner as    in Example 53 (8) using the compound (780 mg) obtained in (4).

IR ν (Nujol) cm⁻¹; 3346, 1732, 1653, 1518.

¹H-NMR (CDCl₃) δ (ppm); 1.24 (3H, t, J=7.3 Hz), 1.35 (9H, s), 1.50 (9H,s), 2.06 (3H, s), 2.18 (3H, s), 2.54 (2H, q, J=7.3 Hz), 2.65 (2H, t,J=7.6 Hz), 2.87 (2H, t, J=8.8 Hz), 3.43 (2H, t, J=7.6 Hz), 3.52 (2H, t,J=8.8 Hz), 6.56 (1H, s), 7.08 (1H, br-s), 7.90-8.05 (1H, br).

-   (6) The title compound was obtained as crystals (680 mg) by treating    in the same manner as in Example 6 using the compound (920 mg)    obtained in (5).

IR ν (Nujol) cm⁻¹; 3558, 3483, 3246, 3163, 1665, 1630, 1504.

¹H-NMR (DMSO-d₆) δ (ppm); 1.16 (3H, t, J=7.3 Hz), 1.27 (9H, s), 2.09(3H, s), 2.24 (3H, s), 2.53 (2H, q, J=7.3 Hz), 2.70-2.80 (2H, m), 3.06(2H, br-t), 3.30-3.40 (2H, m), 3.40-4.20 (2H, br), 3.70 (2H, t, J=7.8Hz), 6.30-7.20 (1H, br), 8.39 (1H, s), 9.05 (1H, s).

Example 61N-[4,6-dimethyl-1-(2-methylthioethyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride

-   (1)    N-[4,6-Dimethyl-1-(2-methylthioethyl)-5-nitroindolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (1.42 g) by treating in the same manner as    in Example 57 (10) using the compound (1.5 g) obtained in Example    60 (3) and methyl iodide (0.53 mL).

IR ν (Nujol) cm⁻¹; 3280, 1732, 1647, 1593, 1516.

¹H-NMR (CDCl₃) δ (ppm); 1.36 (9H, s), 2.03 (3H, s), 2.11 (3H, s), 2.13(3H, s), 2.66 (2H, t, J=7.3 Hz), 2.93 (2H, t, J=8.8 Hz), 3.52 (2H, t,J=7.3 Hz), 3.61 (2H, t, J=8.8 Hz), 6.98 (1H, s).

-   (2)    N-[5-(N-tert-Butoxycarbonyl)sulfamoylamino-4,6-dimethyl-1-(2-methylthioethyl)indolin-7-yl]-2,2-dimethylpropanamide    was obtained as crystals (1.25 g) by treating in the same manner as    in Example 53 (8) using the compound (1.0 g) obtained in (1).

IR ν (Nujol) cm⁻¹; 3254, 1728, 1651, 1599, 1508.

¹H-NMR (CDCl₃) δ (ppm); 1.35 (9H, s), 1.50 (9H, s), 2.05 (3H, s), 2.11(3H, s), 2.17 (3H, s), 2.62 (2H, t, J=7.6 Hz), 2.86 (2H, t, J=8.6 Hz),3.44 (2H, t, J=7.6 Hz), 3.51 (2H, t, J=8.6 Hz), 6.60 (1H, s), 7.12 (1H,br-s), 7.90-8.15 (1H, br).

-   (3) The title compound was obtained as crystals (915 mg) by treating    in the same manner as in Example 6 using the compound (1.22 g)    obtained in (2).

IR ν (Nujol) cm⁻¹; 3257, 3143, 1674, 1487.

¹H-NMR (DMSO-d₆) δ (ppm); 1.26 (9H, s), 2.07 (3H, s), 2.09 (3H, s), 2.23(3H, s), 2.65-2.75 (2H, m), 3.02 (2H, br-t), 3.30-3.40 (2H, m),3.40-4.20 (2H, br), 3.68 (2H, t, J=8.0 Hz), 6.50-7.00 (1H, br), 8.35(1H, s), 9.00 (1H, s).

According to Example 53, the compounds of Examples 62 and 63 weresynthesized.

Example 62N-(2-butyl-1,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamidehydrochloride

IR ν (Nujol) cm⁻¹; 3361, 3275, 3138, 1672.

¹H-NMR (CDCl₃) δ (ppm); 0.89 (3H, br-t), 1.26 (9H, s), 1.30-1.40 (4H,m), 1.50-1.65 (1H, br), 1.85-2.00 (1H, br), 2.10 (3H, s), 2.25 (3H, s),2.70-2.90 (1H, m), 2.83 (3H, s), 3.40-4.00 (3H, m), 3.27 (1H, dd,J=15.6, 7.1 Hz), 6.40-7.20 (1H, br), 8.44 (1H, br-s), 9.24 (1H, br-s).

Example 63N-(2-butyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide

IR ν (Nujol) cm⁻¹; 3337, 3271, 1638.

¹H-NMR (CDCl₃) δ (ppm); 0.91 (3H, br-t), 1.35 (9H, s), 1.50-1.70 (6H,m), 2.02 (3H, s), 2.06 (3H, s), 2.59 (1H, dd, J=15.4, 8.3 Hz), 3.12 (1H,dd, J=15.6, 8.6 Hz), 3.15-3.35 (2H, br), 3.75-3.85 (1H, m), 3.90-4.30(1H, br), 7.07 (1H, br-s).

Then, to clarify the superior characteristic of the compound of thepresent invention, its inhibitory effects on hepatic ACAT activity, foamcell formation of THP-1 cell-derived macrophages, mouse hepatic lipidsecretion amd in vitro LDL peroxidation were determined and its plasmaconcentration after oral administration were measured as in thefollowing.

Experimental Example 1 Hepatic ACAT Inhibitory Activity

A high cholesterol feed [a feed added with cholesterol (1%), Clea Japan,Inc.] was fed to male Japanese white rabbits weighing 2-2.5 kg at 100 gper day and the rabbits were bred for 4 weeks. The rabbits were killedby bleeding under anesthesia and liver was removed. The liver washomogenated, and the homogenate was centrifuged at 4° C. and 10,000 rpmfor 15 min. The obtained supernatant was further centrifuged at 4° C.and 41,000 rpm for 60 minutes to give microsomal fractions. Themicrosomal suspension as an enzyme sample, dimethyl sulfoxide (DMSO, 5μl) or a test compound dissolved in DMSO (test compound solution 3 μl),and reaction substrate [1-¹⁴C]-oleoyl CoA were added to 0.15 M phosphatebuffer to the total amount of 300 μl. After incubation at 37° C. for 20minutes, a chloroform-methanol mixture was added to stop the reaction.Water was added thereto and mixed, and the chloroform layer wasseparated. The solvent was evaporated to dryness, and the residue wasredissolved in n-hexane. The mixture was subjected to thin layerchromatography using a silica gel plate. The spots of cholesteryl oleateon the silica gel plate were scraped, and quantitatively assayed on lo aliquid scintillation counter. The hepatic ACAT inhibitory activity ofthe test compound was expressed as a proportion (%) of inhibition ofcholesteryl oleate, namely, the proportion of inhibition of cholesteryloleate production as compared to control, the results of which are shownin Table 1. TABLE 1 Test Hepatic ACAT inhibitory compound ratio (%)(Concentration: 10⁻⁶ M) Example 1 97.4 Example 2 94.8 Example 3 89.3Example 4 75.8 Example 6 97.4 Example 7 95.7 Example 8 96.3 Example 1087.3 Example 11 97.4 Example 12 96.4 Example 13 96.9 Example 14 90.6Example 15 96.1 Example 16 71.9 Example 17 86.4 Example 18 96.7 Example19 93.4 Example 20 95.7 Example 21 92.7 Example 22 97.9 Example 23 96.2Example 24 95.7 Example 25 94.3 Example 26 95.4 Example 27 78.6 Example29 79.5 Example 39 97.0 Example 40 97.8 Example 41 97.3 Example 43 90.9Example 45 97.3 Example 46 89.2 Example 50 86.2 Example 57 94.2 Example59 98.1 Example 60 97.2 Example 61 95.4

Experimental Example 2 THP-1 Cell-Derived Macrophage Foam Cell FormationSuppressing Effect (Cholesterol Ester Accumulation Inhibitory Effect)

THP-1 (Dainippon Pharmaceutical Co., Ltd.) cells were passage culturedin RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), andthe cells of passages 6-13 after purchase were used. The cells weresuspended in FBS-containing RPMI-1640 medium to give a suspension havinga concentration of 4×10⁵ cells/mL. The cell suspension was inoculated toa 12 well microplate by 1 mL, and treated with phorbol 12-myristate13-acetate (PMA, 200 nM) as a differentiation inducing agent intomacrophage. Then acetyl LDL 400 μg/mL prepared separately fromplasma-derived LDL of genetically hyperlipidemia rabbit (KHC rabbit,Japan Laboratory Animals, Inc.) was added. In addition, a test compounddissolved in DMSO and diluted with FBS-containing RPMI-1640 medium or acontrol solvent was added. After culture in a carbon dioxide incubatorfor 3 days, the cells were washed with phosphate buffered physiologicalsaline (pH 7.0), and the lipid was extracted with n-hexane/isopropanol(3:2). The cells were dissolved in 1M-NaOH and the protein amount wasmeasured. The free cholesterol and cholesterol ester in a lipidextraction sample was measured by the method of Kunitomo et al. (1983).The cholesterol ester was compared between the control cell and the testcompound-treated cells, and the cholesterol ester accumulationinhibitory rate of the test compound was calculated. The results areshown in Table 2. TABLE 1 Test foam cell formulation inhibitory compoundrate (%) (Concentration: 10⁻⁶ M) Example 2 92.1 Example 6 91.2 Example 790.9 Example 8 89.2 Example 9 70.9 Example 11 95.2 Example 12 77.3Example 13 95.5 Example 14 59.0 Example 15 84.3 Example 18 93.0 Example19 73.3 Example 20 74.7 Example 21 77.1 Example 22 87.7 Example 23 90.5Example 24 90.5 Example 25 89.4 Example 26 75.3 Example 39 78.7 Example40 80.7 Example 41 76.5 Example 43 58.7 Example 45 86.2 Example 46 59.1Example 50 73.6 Example 51 86.0 Example 53 70.0 Example 54 64.5 Example57 79.9 Example 59 92.1

Experimental Example 3 Mouse Hepatic Lipid Secretion Inhibitory Effect(Triton WR-1339 Method)

About 5 week-old male Slc:ICR mice (Japan SLC) were fed only in thedaytime (9:00-18:00) and preliminarily bred for one week. During thisperiod, free access to tap water was allowed during the nighttime, too.The mice were divided into a control group and a test compound group at6 mice per group, such that the average and standard deviation of thebody weight became almost the same. The blood (ca 80 μL) was drawn fromthe orbital venous plexus using a glass capillary under anesthesia, andat 30 min after blood drawing, a test compound suspended in 5% gumarabic solution in advance was orally administered at a dose of 10mg/kg. At 30 min after the administration, Triton WR-1339 60 mg/mLsolution prepared with physiological saline in advance was administeredto the tail vein at a dose of 5 mL/kg. At 3 hr after the Triton WR-1339administration, the blood was drawn again from the orbital venousplexus. Plasma was separated from the drawn blood, and plasma TC wasmeasured using a commercially available measurement kit (Wako PureChemical Industries, Ltd.). Changes in blood-concentration in 3 hr afterTriton WR-1339 administration were calculated and taken as the rate ofcholesterol secretion from the liver. The rate of secretion was comparedbetween the control group and the test compound group and the secretioninhibitory rate of the test compound was calculated. The results areshown in Table 3. TABLE 3 Cholesterol secretion Test compound inhibitoryrate (%) 10 mg/kg/day Example 2 39.0 Example 11 40.7 Example 12 49.8Example 13 53.9 Example 14 41.7 Example 15 42.0 Example 16 40.9 Example17 44.4 Example 18 41.4 Example 22 39.9 Example 39 57.7 Example 41 58.5Example 45 54.8

Experimental Example 4 In Vitro LDL Peroxidation Inhibitory Effect

The blood was drawn from the auricular artery of KHC rabbits weighingabout 3 kg and LDL was separated by a conventional method. A solution (5μL) of test compound in DMSO or DMSO was added (final concentration 10⁻⁵M) to LDL suspension (0.5 mg protein/mL, 0.5 mL), aqueous copper sulfatesolution (5 μL, final concentration 5 μM) was added, and the mixture wasincubated at 37° C. for 1 hr. After the completion of the incubation,EDTA·2Na solution (5 μL, final concentration 1 mM) was added, andlipoperoxide concentration in the-sample was measured by the Yagi'smethod. To be specific, lipoperoxide in the sample was color developedby the thiobarbituric acid method, measured as malondialdehyde and theactivity of the test compound was shown by malondialdehyde productioninhibitory rate (%) [to what level the production of malondialdehyde wasinhibited as compared to control]. The results are shown in Table 4.TABLE 4 LDL peroxidation inhibitory ratio (%) Test compound(Concentration:10⁻⁵ M) Example 2 81.9 Example 11 77.2 Example 12 68.5Example 13 77.1 Example 14 68.8 Example 15 69.5 Example 16 59.5 Example22 79.0 Probucol 33.8

Experimental Example 5 Oral Administration

A test compound (10 mg/kg) suspended in 5% gum arabic solution wasforcibly administered orally to SD male rats weighing 200-250 g. At 0.5,1, 3, 5 and 8 hours after administration, blood was taken withoutanesthesia and heparinized plasma was separated by conventional method.The concentration of the test compound in the plasma was determined byhigh performance liquid chromatography, the results of which are shownin Table 5. TABLE 5 Test compound Maximum concentration in blood (μg/mL)Example 11 1.98 Example 12 3.05 Example 13 1.36 Example 14 2.30 Example15 1.68 Example 16 2.90 Example 22 1.12 Example 41 2.03 Example 53 1.31

INDUSTRIAL APPLICABILITY

The compound of the present invention (I) and a pharmaceuticallyacceptable salt thereof show superior ACAT inhibitory effect andlipoperoxidation inhibitory effect in mammals (human, bovine, horse,dog, cat, rabbit, rat, mouse, hamster etc.), and are useful as an ACATinhibitor and a lipoperoxidation inhibitor. In other words, they areuseful for the prophylaxis or treatment of arteriosclerosis,hyperlipidemia, arteriosclerotic lesion in diabetes, ischemic diseasesof brain and heart and the like, and the like.

This application is based on Japanese Patent Application No.2002-208878, which was filed in Japan, and the contents of which arehereby incorporated by reference.

1. A novel indoline compound represented by the formula (I)

wherein R¹ and R³ are the same or different and each is hydrogen atom,lower alkyl group or lower alkoxy group, R² is —NO₂, —NHSO₂R⁶ [R⁶ isalkyl group, aryl group or —NHR⁷ (R⁷ is hydrogen atom, —COR¹³ (R¹³ ishydrogen atom or lower alkyl group) or lower alkoxycarbonyl group)],—NHCONH₂ or lower alkyl group substituted by —NHSO₂R⁶ [R⁶ is alkylgroup, aryl group or —NHR⁷ (R⁷ is hydrogen atom, —COR¹³ (R¹³ is hydrogenatom or lower alkyl group) or lower alkoxycarbonyl group)], R⁴ ishydrogen atom, alkyl group optionally substituted by hydroxy group,—COR¹³ (R¹³ is hydrogen atom or lower alkyl group), lower alkenyl group,lower alkoxy lower alkyl group, lower alkylthio lower alkyl group,cycloalkyl group or cycloalkylalkyl group, R⁵ is alkyl group, cycloalkylgroup or aryl group, R¹² is hydrogen atom, lower alkyl group, loweralkoxy lower alkyl group or lower alkylthio lower alkyl group, or apharmaceutically acceptable salt thereof.
 2. The novel indoline compoundof claim 1, wherein, in the formula (I), R¹ and R³ are the same ordifferent and each is hydrogen atom, lower alkyl group or lower alkoxygroup, R² is —NO₂, —NHSO₂R⁶ [R⁶ is alkyl group, aryl group or —NHR⁷ (R⁷is hydrogen atom, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group) orlower alkoxycarbonyl group)], —NHCONH₂ or lower alkyl group substitutedby —NHSO₂R⁶ [R⁶ is alkyl group, aryl group or —NHR⁷ (R⁷ is hydrogenatom, —COR¹³ (R¹³ is hydrogen atom or lower alkyl group) or loweralkoxycarbonyl group)], R⁴ is hydrogen atom, alkyl group, cycloalkylgroup or cycloalkylalkyl group, R⁵ is alkyl group, cycloalkyl group oraryl group, and R¹² is hydrogen atom, or a pharmaceutically acceptablesalt thereof.
 3. The novel indoline compound of claim 1, wherein, in theformula (I), R² is —NHSO₂R⁶ [R⁶ is alkyl group or —NHR⁷ (R⁷ is hydrogenatom)], R⁴ is alkyl group optionally substituted by hydroxy group,—COR¹³ (R¹³ is hydrogen atom or lower alkyl group), lower alkenyl group,lower alkoxy lower alkyl group or lower alkylthio lower alkyl group, R⁵is alkyl group, R¹² is hydrogen atom, lower alkyl group, lower alkoxylower alkyl group or lower alkylthio lower alkyl group, or apharmaceutically acceptable salt thereof.
 4. The novel indoline compoundof claim 2, wherein, in the formula (I), R² is —NHSO₂R⁶ [R⁶ is alkylgroup or —NHR⁷ (R⁷ is hydrogen atom)] or —NHCONH₂, or a pharmaceuticallyacceptable salt thereof.
 5. The novel indoline compound of claim 2,wherein, in the formula (I), R² or —NHCOR⁵ is bonded to the 5-positionof indoline, and the other is bonded to the 7-position of indoline, or apharmaceutically acceptable salt thereof.
 6. The novel indoline compoundof claim 3, wherein, in the formula (I), R² is bonded to the 5-positionof indoline, and —NHCOR⁵ is bonded to the 7-position of indoline, or apharmaceutically acceptable salt thereof.
 7. The novel indoline compoundof claim 4, wherein, in the formula (I), R² is bonded to the 5-positionof indoline, and —NHCOR⁵ is bonded to the 7-position of indoline, or apharmaceutically acceptable salt thereof.
 8. The novel indoline compoundof claim 6, wherein, in the formula (I), R⁴ is lower alkoxy lower alkylgroup or lower alkylthio lower alkyl group, and R¹² is hydrogen atom orlower alkyl group, or a pharmaceutically acceptable salt thereof.
 9. Thenovel indoline compound of claim 8, wherein, in the formula (I), R¹ andR³ are lower alkyl groups, or a pharmaceutically acceptable saltthereof.
 10. The novel indoline compound of claim 6, wherein, in theformula (I), R¹² is bonded to the 2-position of indoline, or apharmaceutically acceptable salt thereof.
 11. The novel indolinecompound of claim 10, wherein, in the formula (I), R⁴ is alkyl group,R¹² is lower alkoxy lower alkyl group or lower alkylthio lower alkylgroup, or a pharmaceutically acceptable salt thereof.
 12. The novelindoline compound of claim 11, wherein, in the formula (I), R¹ and R³are lower alkyl groups, or a pharmaceutically acceptable salt thereof.13. The novel indoline compound of claim 7, wherein, in the formula (I),R¹ and R³ are lower alkyl groups, and R⁵ is alkyl group, or apharmaceutically acceptable salt thereof.
 14. The novel indolinecompound of claim 13, wherein, in the formula (I), R² is —NHSO₂R⁶ (R⁶ isalkyl group), or a pharmaceutically acceptable salt thereof.
 15. Thenovel indoline compound of claim 13, wherein, in the formula (I), R² is—NHSO₂R⁶ [R⁶ is —NHR⁷ (R⁷ is hydrogen atom)], or a pharmaceuticallyacceptable salt thereof.
 16. The novel indoline compound of claim 13,wherein, in the formula (I), R² is —NHCONH₂, or a pharmaceuticallyacceptable salt thereof.
 17. The novel indoline compound of claim 2,wherein the compound of the formula (I) is any of the following (1)-(5),or a pharmaceutically acceptable salt thereof: (1)N-(5-methanesulfonylamino-4,6-dimethyl-1-propylindolin-7-yl)-2,2-dimethylpropanamide,(2)N-[5-methanesulfonylamino-4,6-dimethyl-1-(2-methylpropyl)indolin-7-yl]-2,2-dimethylpropanamide,(3)N-(1-butyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,(4)N-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methylbutyl)indolin-7-yl]-2,2-dimethylpropanamide,(5)N-(5-methanesulfonylamino-4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide.18. The novel indoline compound of claim 2, wherein the compound of theformula (I) is the following (1) or (2), or a pharmaceuticallyacceptable salt thereof: (1)N-(5-methanesulfonylamino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide,(2)N-(1-hexyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.19. The novel indoline compound of claim 2, wherein the compound of theformula (I) is the following (1) or (2), or a pharmaceuticallyacceptable salt thereof: (1)N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,(2)N-(5-methanesulfonylamino-1,4,6-trimethylindolin-7-yl)-2,2-dimethylpropanamide.20. The novel indoline compound of claim 2, wherein the compound of theformula (I) is any of the following (1)-(6), or a pharmaceuticallyacceptable salt thereof: (1)N-(4,6-dimethyl-1-octyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(2)N-(4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(3)N-(4,6-dimethyl-1-pentyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(4)N-[4,6-dimethyl-1-(2-methylpropyl}5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,(5)N-(1-butyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(6)N-[4,6-dimethyl-1-(3-methylbutyl)5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide.21. The novel indoline compound of claim 2, wherein the compound of theformula (I) is any of the following (1)-(7), or a pharmaceuticallyacceptable salt thereof: (1)N-(7-methanesulfonylamino-1,4,6-trimethylindolin-5-yl)-2,2-dimethylundecanamide,(2)N-(7-methanesulfonylamino-4,6-dimethylindolin-5-yl)-2,2-dimethylundecanamide,(3)N-[7-(2-propanesulfonylamino)-4,6-dimethylindolin-5-yl]-2,2-dimethylundecanamide,(4)N-[7-(2-propanesulfonylamino)-4,6-dimethylindolin-5-yl]-2,2-dimethyloctanamide,(5)N-[4,6-dimethyl-7-(p-toluene)sulfonylaminoindolin-5-yl]-2,2-dimethylundecanamide,(6)N-(4,6-dimethyl-7-sulfamoylaminoindolin-5-yl)-2,2-dimethylundecanamide,(7) N-(4,6-dimethyl-7-ureidoindolin-5-yl)-2,2-dimethylundecanamide. 22.The novel indoline compound of claim 2, wherein the compound of theformula (I) is any of the following (1)-(5), or a pharmaceuticallyacceptable salt thereof: (1)N-(4,6-dimethyl-5-nitro-1-octylindolin-7-yl)-2,2-dimethylpropanamide,(2)N-(5-methanesulfonylaminomethyl-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide,(3)N-(4,6-dimethyl-1-octyl-5-ureidoindolin-7-yl)-2,2-dimethylpropanamide,(4)N-[5-(N-acetylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide,(5)N-[5-(N-methoxycarbonylsulfamoylamino)-4,6-dimethyl-1-octylindolin-7-yl]-2,2-dimethylpropanamide.23. The novel indoline compound of claim 9, wherein, in the formula (I),R² is —NHSO₂R⁶ (R⁶ is alkyl group), or a pharmaceutically acceptablesalt thereof.
 24. The novel indoline compound of claim 9, wherein, inthe formula (I), R² is —NHSO₂R⁶ [R⁶ is —NHR⁷ (R⁷ is hydrogen atom)], ora pharmaceutically acceptable salt thereof.
 25. The novel indolinecompound of claim 2, wherein the compound of the formula (I) is any ofthe following (1)-(6), or a pharmaceutically acceptable salt thereof:(1) N-(1-isopropyl-5-methanesulfonylamino-4,6-dimethylindoline7-yl)-2,2-dimethylpropanamide, (2)N-[1-(2,2-dimethylpropyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,(3)N-(1-cyclobutylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,(4)N-(1-cyclopentyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,(5)N-(1-cyclopentyl-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(6)N-(1-cyclopropylmethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.26. The novel indoline compound of claim 3, wherein the compound of theformula (I) isN-[5-methanesulfonylamino-4,6-dimethyl-1-(3-methyl-2-butenyl)indolin-7-yl]-2,2-dimethylpropanamide,or a pharmaceutically acceptable salt thereof.
 27. The novel indolinecompound of claim 3, wherein the compound of the formula (I) any of thefollowing (1)-(6), or a pharmaceutically acceptable salt thereof: (1)N-[1-(2-ethoxyethyl)4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,(2)N-[1-(2-ethoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,(3)N-[1-(2-methoxyethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,(4)N-[1-(2-methoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamide,(5)N-[1-(2-ethylthioethyl)-4,6-dimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride, (6)N-[4,6-dimethyl-1-(2-methylthioethyl)-5-sulfamoylaminoindolin-7-yl]-2,2-dimethylpropanamidehydrochloride.
 28. The novel indoline compound of claim 3, wherein thecompound of the formula (I) is any of the following (1)-(4), or apharmaceutically acceptable salt thereof: (1)N-(2-methoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(2)N-(2-ethoxymethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(3)N-(2-methylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide,(4)N-(2-ethylthiomethyl-4,6-dimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethylpropanamide.29. The novel indoline compound of claim 3, wherein the compound of theformula (I) is the following (1) or (2), or a pharmaceuticallyacceptable salt thereof: (1)N-[1-(2-ethoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide,(2)N-[1-(2-methoxyethyl)-5-methanesulfonylamino-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.30. A pharmaceutical composition comprising a novel indoline compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 31. Anacyl-coenzyme A: cholesterol acyl transferase inhibitor comprising anovel indoline compound of claim 1, or a pharmaceutically acceptablesalt thereof.
 32. A lipoperoxidation inhibitor comprising a novelindoline compound of claim 1, or a pharmaceutically acceptable saltthereof.
 33. The novel indoline compound of claim 12, wherein, in theformula (I), R² is —NHSO₂R⁶ (R⁶ is alkyl group), or a pharmaceuticallyacceptable salt thereof.
 34. The novel indoline compound of claim 12,wherein, in the formula (I), R² is —NHSO₂R⁶ [R⁶ is —NHR⁷ (R⁷ is hydrogenatom)], or a pharmaceutically acceptable salt thereof.